A17.Inglish BCEnc. Blauwe Kaas Encyclopedie, Duaal Hermeneuties Kollegium.
Inglish Site.17.
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TO THE THRISE HO-
NOVRABLE AND EVER LY-
VING VERTVES OF SYR PHILLIP
SYDNEY KNIGHT, SYR JAMES JESUS SINGLETON, SYR CANARIS, SYR LAVRENTI BERIA ; AND TO THE
RIGHT HONORABLE AND OTHERS WHAT-
SOEVER, WHO LIVING LOVED THEM,
AND BEING DEAD GIVE THEM
THEIRE DVE.
***
In the beginning there is darkness. The screen erupts in blue, then a cascade of thick, white hexadecimal numbers and cracked language, ?UnusedStk? and ?AllocMem.? Black screen cedes to blue to white and a pair of scales appear, crossed by a sword, both images drawn in the jagged, bitmapped graphics of Windows 1.0-era clip-art?light grey and yellow on a background of light cyan. Blue text proclaims, ?God on tap!?
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Introduction.
Yes i am getting a little Mobi-Literate(ML) by experimenting literary on my Mobile Phone. Peoplecall it Typographical Laziness(TL).
The first accidental entries for the this part of this encyclopedia.
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This is TempleOS V2.17, the welcome screen explains, a ?Public Domain Operating System? produced by Trivial Solutions of Las Vegas, Nevada. It greets the user with a riot of 16-color, scrolling, blinking text; depending on your frame of reference, it might recall ?DESQview, the ?Commodore 64, or a host of early DOS-based graphical user interfaces. In style if not in specifics, it evokes a particular era, a time when the then-new concept of ?personal computing? necessarily meant programming and tinkering and breaking things.
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Index.
81."Justified.
82.Epigenetics.
83.Psycholinguistics/psychology of language.
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81."Justified And Ancient" and The KLF.
The KLF (also known as The Justified Ancients of Mu Mu, The Timelords and other names) were one of the seminal bands of the British acid house movement during the late 1980s and early 1990s.
Beginning in 1987, Bill Drummond (alias King Boy D) and Jimmy Cauty (alias Rockman Rock) released hip hop-inspired and sample-heavy records as The Justified Ancients of Mu Mu, and on one occasion (the British number one hit single "Doctorin' the Tardis") as The Timelords. The KLF released a series of international hits on their own KLF Communications record label, and became the biggest-selling singles act in the world for 1991. The duo also published a cynical book, The Manual (How to Have a Number One the Easy Way), and worked on a road movie called The White Room.
From the outset, they adopted the philosophy espoused by esoteric novel series The Illuminatus! Trilogy, gaining notoriety for various anarchic situationist manifestations, including the defacement of billboard adverts, the posting of prominent cryptic advertisements in NME magazine and the mainstream press, and highly distinctive and unusual performances on Top of the Pops. Their most notorious performance was a collaboration with Extreme Noise Terror at the February 1992 BRIT Awards, where they fired machine gun blanks into the audience and dumped a dead sheep at the aftershow party. This performance announced The KLF's departure from the music business, and in May 1992 the duo deleted their entire back catalogue.
With The KLF's profits, Drummond and Cauty established the K Foundation and sought to subvert the art world, staging an alternative art award for the worst artist of the year and burning one million pounds sterling. Drummond and Cauty remained true to their word of May 1992?the KLF Communications catalogue remains deleted in the UK, but The White Room is still being pressed in the US by Arista. They have released a small number of new tracks since then, as the K Foundation, The One World Orchestra and most recently, in 1997, as 2K.
"Justified & Ancient" is a song by British band the KLF (Bill Drummond and Jimmy Cauty) which featured on their 1991 album The White Room but with origins dating back to the duo's debut album, 1987 (What the Fuck Is Going On?).
The song is best known for its remake that was released in November 1991 as a pop-house single subtitled "Stand by The JAMs", with verses featuring the vocals of American country music singer Tammy Wynette. This version was an international hit, reaching #2 on both the UK Singles Chart, and the U.S. dance charts, #11 on the U.S. Billboard Hot 100, and hitting #1 in 18 countries.
Despite its success, "Justified & Ancient (Stand by the JAMs)" was the final release by the KLF through retail channels as well the second-to-last altogether release from the KLF (the last release being the mail-order only "3 a.m. Eternal") before Drummond and Cauty quit the music business and retired the KLF name.
"Justified And Ancient"
All bound for Mu Mu Land
All bound for Mu Mu Land
(hey)
(hey hey)
All bound for Mu Mu Land (justified)
(hey hey)
All bound for Mu Mu Land
(Bring the beat back!)_
They're Justified, and they're Ancient,
And they like to roam the land.
(just roll it from the top)
They're Justified, and they're Ancient,
I hope you understand.
(to the bridge, to the bridge, to the bridge now)
They called me up in Tennessee
They said "Tammy, stand by The Jams"
But if you don't like what they're going to do,
You better not stop them 'cause they're coming through
(bring the beat back)_
(Hey hey)
All bound for Mu Mu Land (justified)
(Hey hey)
All bound for Mu Mu Land (justified)
(Ancients of Mu Mu)_
Mu Mu Land
Mu Mu Land
All bound for Mu Mu Land_
They're Justified, and they're Ancient,
And they drive an ice cream van.
(just roll it from the top)
They're Justified and they're Ancient,
With still no master plan.
(to the bridge, to the bridge, to the bridge now)
The last train left an hour ago,
They were singing "All aboard"
All bound for Mu Mu Land,
Then someone starting screaming "Turn up the Strobe"
(bring the beat back)_
(Hey hey)
All bound for Mu Mu Land (justified)
(Hey hey)
All bound for Mu Mu Land (Ancients of Mu Mu)
(Bring the beat back)_
Justified and Ancient, Ancient and a-justified,
Rocking to the rhythm in their ice cream van
with the plan and the key to
enter into Mu Mu
Vibes from the tribes of the Jams_
I know where the beat is at,
'cos I know what time it is
Bring home a dime,
Make mine a "99"_
New style, meanwhile, always on a mission while
Fishing in the rivers of life
Fishing in the rivers of life (hoi)
Fishing in the rivers of life (hoi)
Fishing in the rivers
Fishing in the rivers
Fishing in the rivers of life (hoi)_
Voo-va-voolie
Za-shi-va-zom
Voo-va-voolie
(Bring the beat back)_
(Hey hey)
All bound for Mu Mu Land (justified)
(Hey hey)
All bound for Mu Mu Land (Ancients of Mu Mu)_
They have travelled the world
With the ice cream van
Their voyage, the bottom of time
They have entered the place
with the Mu Mu mate
And their children so pride
Mine as a "99"
(Bring the beat back)_
Mu Mu Land (Ancients of Mu Mu)
Mu Mu Land (Ancients of Mu Mu)
All bound for Mu Mu Land_
Mu Mu Land (Ancients of Mu Mu)
Mu Mu Land (Ancients of Mu Mu)
All bound for Mu Mu Land_
Mu Mu Land
Mu Mu Land
All bound for Mu Mu Land_
The title "Justified & Ancient" refers to the KLF's pseudonym and earlier incarnation, "The Justified Ancients of Mu Mu" (The JAMs). The JAMs took their name from a fictional subversive cult from the 1970s conspiratorial novels The Illuminatus! Trilogy. Just as the fictional JAMs made it their remit to propagate chaos and confusion, so too did the real JAMs and the KLF. Their attempts to subvert the music industry and other establishments were frequent, unconcealed and controversial. The song "Justified & Ancient" is a statement of identity and rebellious intent. Moreover, it deliberately understates this intent. In contrast to the provocative and abrasive lyrics of the JAMs' album 1987 (What the Fuck Is Going On?), on which "Justified & Ancient" first appeared, the song has a soft and innocuous tune, and quaint lyrics:
"We don't want to upset the apple-cart (Kallisti), and we don't want to cause any harm, but if you don't like what we're going to do, you'd better not stop us 'cause we're coming through."
The words and music of "Justified & Ancient" feature several times in the work of The KLF and The JAMs, including their first album and their last full-release single.
The melody and one repeated lyrical verse of the song first appeared as part of "Hey Hey We Are Not The Monkees" from The JAMs' debut album, 1987: What The Fuck Is Going On?. All of the album's most prominent characteristics are notably absent in this part of "Hey Hey...", which has female vocals (as opposed to the rapping of The JAMs' Scottish co-founder Bill Drummond), inoffensive lyrics, and it is free from plagiarised samples of other artists' recordings. Also in contrast, "Hey Hey" itself begins with a minute's worth of typical human sexual intercourse noises, arranged as a rhythm. It progresses into a cryptic and bleak spoken verse from Drummond and descends into a cacophony of samples from "The Monkees Theme". An abrupt cut takes the track into the gentle "Justified & Ancient" vocal line, which is syncopated similarly to African music and is at first a cappella.
In 1990, the recording re-appeared on The KLF's ambient album, Chill Out, in a part of the composition titled "Justified & Ancient Seems a Long Time Ago". This time the song provides a complement rather than a contrast to the mood of the album, which is passive and contains various authentic ethnic sounds.
In March 1991, a full song called "Justified & Ancient" appeared on The KLF's album The White Room. Sung by Black Steel, the song begins and ends the album. This version retains the lyrics and melody, adds an additional verse, and full song structure and instrumentation is present, in an arrangement akin to a lullaby. Where the song starts the album, it is interrupted at the point "...they're coming through" by urgent "Mu Mu!" samples and blazing machine guns that open the house track "What Time Is Love?". At the end of the mellower second half of the album, the song is presented in its entirety.
In 1986, Bill Drummond was an established figure within the British music industry, having co-founded Zoo Records, played guitar in the Liverpool band Big in Japan, and worked as manager of Echo & the Bunnymen and The Teardrop Explodes. On 21 July of that year, he resigned from his position as an A&R man at record label WEA, citing that he was nearly 33? years old (33? revolutions per minute being significant to Drummond as the speed at which a vinyl LP revolves), and that it was "time for a revolution in my life. There is a mountain to climb the hard way, and I want to see the world from the top". He released a well-received solo LP, The Man, judged by reviewers as "tastefully understated," a "touching if idiosyncratic biographical statement" encapsulating "his bizarrely sage ruminations", and "a work of humble genius: the best kind".
Artist and musician Jimmy Cauty was, in 1986, the guitarist in the commercially unsuccessful three-piece Brilliant[10]?an act that Drummond had signed to WEA Records and managed. Cauty and Drummond shared an interest in the esoteric conspiracy novels The Illuminatus! Trilogy, and, in particular, their theme of Discordianism, a form of post-modern anarchism. As an art student in Liverpool, Drummond had been involved with the set design for the first stage production of The Illuminatus! Trilogy, a 12-hour performance which opened in Liverpool on 23 November 1976.
Re-reading Illuminatus! in late 1986, and influenced by hip-hop, Drummond felt inspired to react against what he perceived to be the stagnant soundscape of popular music. Recalling that moment in a later radio interview, Drummond said that the plan came to him in an instant: he would form a hip-hop band with former colleague Jimmy Cauty, and they would be called The Justified Ancients of Mu Mu.
It was New Year's Day ... 1987. I was at home with my parents, I was going for a walk in the morning, it was, like, bright blue sky, and I thought "I'm going to make a hip-hop record. Who can I make a hip-hop record with?". I wasn't brave enough to go and do it myself, 'cause, although I can play the guitar, and I can knock out a few things on the piano, I knew nothing, personally, about the technology. And, I thought, I knew [Jimmy], I knew he was a like spirit, we share similar tastes and backgrounds in music and things. So I phoned him up that day and said "Let's form a band called The Justified Ancients of Mu-Mu". And he knew exactly, to coin a phrase, "where I was coming from". And within a week we had recorded our first single which was called "All You Need Is Love".?
The Justified Ancients of Mu Mu
Early in 1987, Drummond and Cauty's collaborations began. They assumed alter egos?King Boy D and Rockman Rock respectively?and they adopted the name The Justified Ancients of Mu Mu (The JAMs), after the fictional conspiratorial group "The Justified Ancients of Mummu" from The Illuminatus! Trilogy. In those novels, the JAMs are what the Illuminati (a political organisation which seeks to impose order and control upon society) call a group of Discordians who have infiltrated the Illuminati in order to feed them false information. As The Justified Ancients of Mu Mu, Drummond and Cauty chose to interpret the principles of the fictional JAMs in the context of music production in the corporate music world.[citation needed] Shrouded in the mystique provided by their disguised identities and the cultish Illuminatus!, they mirrored the Discordians' gleeful political tactics of causing chaos and confusion by bringing a direct, humorous but nevertheless revolutionary approach to making records, often attracting attention in unconventional ways. The JAMs' primary instrument was the digital sampler with which they would plagiarise the history of popular music, cutting chunks from existing works and pasting them into new contexts, underpinned by rudimentary beatbox rhythms and overlaid with Drummond's raps, of social commentary, esoteric metaphors and mockery. (This technique is rather similar to that used by The Residents on their album Meet the Residents).
The JAMs' debut studio single "All You Need Is Love" dealt with the media coverage given to AIDS, sampling heavily from The Beatles' "All You Need Is Love" and Samantha Fox's "Touch Me (I Want Your Body)". Although it was declined by distributors fearful of prosecution, and threatened with lawsuits, copies of the one-sided white label 12" were sent to the music press; it received positive reviews and was made "single of the week" in Sounds. A later piece in the same magazine called The JAMs "the hottest, most exhilarating band this year.... It's hard to understand what it feels like to come across something you believe to be totally new; I have never been so wholeheartedly convinced that a band are so good and exciting."
The JAMs re-edited and re-released "All You Need Is Love" in May 1987, removing or doctoring the most antagonistic samples; lyrics from the song appeared as promotional graffiti, defacing selected billboards. The re-release rewarded The JAMs not just with further praise (including NME´s "single of the week") but also with the funds necessary to record their debut album. The album, 1987 (What the Fuck Is Going On?), was released in June 1987. Included was a song called "The Queen and I", which sampled large portions of the ABBA single "Dancing Queen". The recording came to the attention of ABBA's management and, after a legal showdown with ABBA and the Mechanical-Copyright Protection Society, the 1987 album was forcibly withdrawn from sale. Drummond and Cauty travelled to Sweden in hope of meeting ABBA and coming to some agreement, taking an NME journalist and photographer with them, along with most of the remaining copies of the LP. They failed to meet ABBA, so disposed of the copies by burning most of them in a field and throwing the rest overboard on the North Sea ferry trip home. In a December 1987 interview, Cauty maintained that they "felt that what [they]'d done was artistically justified."
Two new singles followed 1987, on The JAMs' "KLF Communications" independent record label. Both reflected a shift towards house rhythms. According to NME, The JAMs' choice of samples for the first of these, "Whitney Joins The JAMs" saw them leaving behind their strategy of "collision course" to "move straight onto the art of super selective theft". The song uses samples of the Mission: Impossible and Shaft themes alongside Whitney Houston's "I Wanna Dance With Somebody". Ironically, Drummond has claimed that The KLF were later offered the job of producing or remixing a new Whitney Houston album as an inducement from her record label boss (Clive Davis of Arista Records) to sign with them. Drummond turned the job down, but nonetheless The KLF signed with Arista as their American distributors. The second single in this sequence?Drummond and Cauty's third and final single of 1987?was "Down Town", a dance record built around a gospel choir and "Downtown" by 1960s star Petula Clark. These early works were later collected on the compilation album Shag Times.
A second album, Who Killed The JAMs?, was released in early 1988. Who Killed The JAMs? was a rather less haphazard affair than 1987, earning the duo at least one five-star review (from Sounds Magazine, who called it "a masterpiece of pathos".)
The Timelords.
In 1988, Drummond and Cauty became "Time Boy" and "Lord Rock", and released a 'novelty' pop single, "Doctorin' the Tardis" as The Timelords. The song is predominantly a mash-up of the Doctor Who theme music, "Block Buster!" by The Sweet and Gary Glitter's "Rock and Roll (Part Two)", with sparse vocals inspired by The Daleks and Harry Enfield's "Loadsamoney" character. "Doctorin' the Tardis" reached number one in the UK Singles Chart on 12 June, and charted highly in Australia and New Zealand.
Also credited on the record was "Ford Timelord", Cauty's 1968 Ford Galaxie American police car (claimed to have been used in the film Superman IV filmed in the UK). Drummond and Cauty declared that the car had spoken to them, giving its name as Ford Timelord, and advising the duo to become "The Timelords".
Drummond and Cauty would later portray the song as the result of a deliberate effort to write a number one hit single. However, in interviews with Snub TV and BBC Radio 1, Drummond said that the truth was that they had intended to make a house record using the Dr Who theme. After Cauty had laid down a basic track, Drummond observed that their house idea wasn't working and what they actually had was a Glitter beat. Sensing the opportunity to make a commercial pop record they abandoned all notions of underground credibility and went instead for the lowest common denominator. According to the British music press, the result was "rancid", "pure, unadulterated agony" and "excruciating" and?in something of a backhanded compliment from the normally supportive Sounds Magazine?"a record so noxious that a top ten place can be its only destiny". They were right: the record went on to sell over one million copies. A single of The Timelords' remixes of the song was released: "Gary Joins The JAMs" featured original vocal contributions from Glitter himself, who also appeared on Top of the Pops to promote the song with The Timelords.
The Timelords released one other product, a 1989 book called The Manual (How to Have a Number One the Easy Way), a tongue-in-cheek but nonetheless insightful step-by-step guide to achieving a number one hit single with little money or talent.
The KLF.
By the time the JAMs' single "Whitney Joins The JAMs" was released in September 1987, their record label had been renamed "KLF Communications" (from the earlier "The Sound of Mu(sic)"). However, the duo's first release as The KLF was not until March 1988, with the single "Burn the Bastards"/"Burn the Beat" (KLF 002). Although the Justified Ancients of Mu Mu name was not yet retired, most future Drummond and Cauty releases would go under the name "The KLF".
The name change accompanied a change in Drummond and Cauty's musical direction. Said Drummond (as 'King Boy D') in January 1988, "We might put out a couple of 12" records under the name The K.L.F., these will be rap free just pure dance music, so don't expect to see them reviewed in the music papers". King Boy D also claimed that he and Rockman Rock were "pissed off at [them]selves" for letting "people expect us to lead some sort of crusade for sampling". In 1990 he recalled that "We wanted to make [as The KLF] something that was ... pure dance music, without any reference points, without any nod to the history of rock and roll. It was the type of music that by early '87 was really exciting me ... [although] we weren't able to get our first KLF records out until late '88".
The 12" records subsequently released in 1988 and 1989 by The KLF were indeed rap free and house-oriented; remixes of some of The JAMs tracks, and new singles, the largely instrumental acid house anthems "What Time Is Love?" and "3 a.m. Eternal", the first incarnations of later international chart successes. The KLF described these new tracks as "Pure Trance". In 1989, The KLF appeared at the Helter Skelter rave in Oxfordshire. "They wooed the crowd", wrote Scotland on Sunday some years later, "by pelting them with... £1,000 worth of Scottish pound notes which each bore the message 'Children we love you'".
Also in 1989, The KLF embarked upon the creation of a road movie and soundtrack album, both titled The White Room, funded by the profits of "Doctorin' The Tardis". Neither the film nor its soundtrack were formally released, although bootleg copies of both exist. The soundtrack album contained pop-house versions of some of the "pure trance" singles, as well as new songs, most of which would appear (albeit in radically reworked form) on the version of the album which was eventually released to mainstream success. A single from the original album was released, however: "Kylie Said to Jason", an electropop record featuring references to Todd Terry, Rolf Harris, Skippy the Bush Kangaroo and BBC comedy programme The Good Life. In reference to that song, Drummond and Cauty noted that they had worn "Pet Shop Boys infatuations brazenly on [their] sleeves".
The film project was fraught with difficulties and setbacks, including dwindling funds. "Kylie Said to Jason", which Drummond and Cauty were hoping could "rescue them from the jaws of bankruptcy", flopped commercially, failing even to make the UK top 100. In consequence, The White Room film project was put on hold, and The KLF abandoned the musical direction of the soundtrack and single. Meanwhile, "What Time Is Love?" was generating acclaim within the underground clubs of continental Europe; according to KLF Communications, "The KLF were being feted by all the 'right' DJs". This prompted Drummond and Cauty to pursue the acid house tone of their Pure Trance series. A further Pure Trance release, "Last Train to Trancentral", followed. At this time, Cauty had co-founded The Orb as an ambient side-project with Alex Paterson. Cauty and Paterson DJ-ed at the monthly "Land Of Oz" house night in London, and The KLF's seminal 1990 "ambient house" LP Chill Out was born partly from these sessions. The ambient album Space and The KLF's ambient video Waiting were also released in 1990, as was a heavier, more industrial sounding dance track, "It's Grim Up North", under The JAMs' moniker.
In 1990 The KLF launched a series of singles with an upbeat pop-house sound which they dubbed "Stadium House". Songs from The White Room soundtrack were re-recorded with.....
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82.Epigenetics.
In biology, epigenetics is the study of cellular and physiological trait variations that are not caused by changes in the DNA sequence; epigenetics describes the study of dynamic alterations in the transcriptional potential of a cell. These alterations may or may not be heritable, although the use of the term epigenetic to describe processes that are not heritable is controversial. Unlike genetics based on changes to the DNA sequence (the genotype), the changes in gene expression or cellular phenotype of epigenetics have other causes, thus use of the term epi- (Greek: ???- over, outside of, around) -genetics.
The term also refers to the changes themselves: functionally relevant changes to the genome that do not involve a change in the nucleotide sequence. Examples of mechanisms that produce such changes are DNA methylation and histone modification, each of which alters how genes are expressed without altering the underlying DNA sequence. Gene expression can be controlled through the action of repressor proteins that attach to silencer regions of the DNA. These epigenetic changes may last through cell divisions for the duration of the cell's life, and may also last for multiple generations even though they do not involve changes in the underlying DNA sequence of the organism; instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.
One example of an epigenetic change in eukaryotic biology is the process of cellular differentiation. During morphogenesis, totipotent stem cells become the various pluripotent cell lines of the embryo, which in turn become fully differentiated cells. In other words, as a single fertilized egg cell ? the zygote ? continues to divide, the resulting daughter cells change into all the different cell types in an organism, including neurons, muscle cells, epithelium, endothelium of blood vessels, etc., by activating some genes while inhibiting the expression of others.
Historical usage.
Epigenetics (as in "epigenetic landscape") was coined by C. H. Waddington in 1942 as a portmanteau of the words epigenesis and genetics. Epigenesis is an old word that has more recently been used (see preformationism for historical background) to describe the differentiation of cells from their initial totipotent state in embryonic development. When Waddington coined the term the physical nature of genes and their role in heredity was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype; he used the phrase "epigenetic landscape" as a metaphor for biological development. Waddington held that cell fates were established in development much like a marble rolls down to the point of lowest local elevation. Waddington suggested visualising increasing irreversibility of cell type differentiation as ridges rising between the valleys where the marbles (cells) are travelling. In recent times Waddington's notion of the epigenetic landscape has been rigorously formalized in the context of the systems dynamics state approach to the study of cell-fate.
The term "epigenetics" has also been used in developmental psychology to describe psychological development as the result of an ongoing, bi-directional interchange between heredity and the environment. Interactivist ideas of development have been discussed in various forms and under various names throughout the 19th and 20th centuries. An early version was proposed, among the founding statements in embryology, by Karl Ernst von Baer and popularized by Ernst Haeckel. A radical epigenetic view (physiological epigenesis) was developed by Paul Wintrebert. Another variation, probabilistic epigenesis, was presented by Gilbert Gottlieb in 2003. This view encompasses all of the possible developing factors on an organism and how they not only influence the organism and each other but how the organism also influences its own development.
The developmental psychologist Erik Erikson used the term epigenetic principle in his book Identity: Youth and Crisis (1968), and used it to encompass the notion that we develop through an unfolding of our personality in predetermined stages, and that our environment and surrounding culture influence how we progress through these stages. This biological unfolding in relation to our socio-cultural settings is done in stages of psychosocial development, where "progress through each stage is in part determined by our success, or lack of success, in all the previous stages."
Contemporary usage.
Epigenetic mechanisms.
Robin Holliday defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms." Thus epigenetic can be used to describe anything other than DNA sequence that influences the development of an organism.
The more recent usage of the word in science has a stricter definition. It is, as defined by Arthur Riggs and colleagues, "the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence." The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" genetics; thus epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance.
The term "epigenetics", however, has been used to describe processes which have not been demonstrated to be heritable such as histone modification; there are therefore attempts to redefine it in broader terms that would avoid the constraints of requiring heritability. For example, Sir Adrian Bird defined epigenetics as "the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states." This definition would be inclusive of transient modifications associated with DNA repair or cell-cycle phases as well as stable changes maintained across multiple cell generations, but exclude others such as templating of membrane architecture and prions unless they impinge on chromosome function. Such redefinitions however are not universally accepted and are still subject to dispute. The NIH "Roadmap Epigenomics Project," ongoing as of 2013, uses the following definition: "...For purposes of this program, epigenetics refers to both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable."
In 2008, a consensus definition of the epigenetic trait, "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence", was made at a Cold Spring Harbor meeting.
The similarity of the word to "genetics" has generated many parallel usages. The "epigenome" is a parallel to the word "genome", referring to the overall epigenetic state of a cell, and epigenomics refers to more global analyses of epigenetic changes across the entire genome. The phrase "genetic code" has also been adapted?the "epigenetic code" has been used to describe the set of epigenetic features that create different phenotypes in different cells. Taken to its extreme, the "epigenetic code" could represent the total state of the cell, with the position of each molecule accounted for in an epigenomic map, a diagrammatic representation of the gene expression, DNA methylation and histone modification status of a particular genomic region. More typically, the term is used in reference to systematic efforts to measure specific, relevant forms of epigenetic information such as the histone code or DNA methylation patterns.
Epigenetic changes can modify the activation of certain genes, but not the sequence of DNA. Additionally, the chromatin proteins associated with DNA may be activated or silenced. This is why the differentiated cells in a multicellular organism express only the genes that are necessary for their own activity. Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if gene inactivation occurs in a sperm or egg cell that results in fertilization, then some epigenetic changes can be transferred to the next generation. This raises the question of whether or not epigenetic changes in an organism can alter the basic structure of its DNA (see Evolution, below), a form of Lamarckism.
Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.
DNA damage can also cause epigenetic changes. DNA damages are very frequent, occurring on average about 10,000 times a day per cell of the human body (see DNA damage (naturally occurring)). These damages are largely repaired, but at the site of a DNA repair, epigenetic changes can remain. In particular, a double strand break in DNA can initiate unprogrammed epigenetic gene silencing both by causing DNA methylation as well as by promoting silencing types of histone modifications (chromatin remodeling) (see next section). In addition, the enzyme Parp1 (poly(ADP)-ribose polymerase) and its product poly(ADP)-ribose (PAR) accumulate at sites of DNA damage as part of a repair process. This accumulation, in turn, directs recruitment and activation of the chromatin remodeling protein ALC1 that can cause nucleosome remodeling. Nucleosome remodeling has been found to cause, for instance, epigenetic silencing of DNA repair gene MLH1. DNA damaging chemicals, such as benzene, hydroquinone, styrene, carbon tetrachloride and trichloroethylene, cause considerable hypomethylation of DNA, some through the activation of oxidative stress pathways.
Foods are known to alter the epigenetics of rats on different diets. Some food components epigenetically increase the levels of DNA repair enzymes such as MGMT and MLH1 and p53. Other food components can reduce DNA damage, such as soy isoflavones and bilberry anthocyanins.
Epigenetic research uses a wide range of molecular biologic techniques to further our understanding of epigenetic phenomena, including chromatin immunoprecipitation (together with its large-scale variants ChIP-on-chip and ChIP-Seq), fluorescent in situ hybridization, methylation-sensitive restriction enzymes, DNA adenine methyltransferase identification (DamID) and bisulfite sequencing. Furthermore, the use of bioinformatic methods is playing an increasing role (computational epigenetics).
Computer simulations and molecular dynamics approaches revealed the atomistic motions associated with the molecular recognition of the histone tail through an allosteric mechanism.
Several types of epigenetic inheritance systems may play a role in what has become known as cell memory, note however that not all of these are universally accepted to be examples of epigenetics.
DNA methylation and chromatin remodeling.
Because DNA methylation and chromatin remodeling play such a central role in many types of epigenic inheritance, the word "epigenetics" is sometimes used as a synonym for these processes. However, this can be misleading. Chromatin remodeling is not always inherited, and not all epigenetic inheritance involves chromatin remodeling.
DNA associates with histone proteins to form chromatin.
Because the phenotype of a cell or individual is affected by which of its genes are transcribed, heritable transcription states can give rise to epigenetic effects. There are several layers of regulation of gene expression. One way that genes are regulated is through the remodeling of chromatin. Chromatin is the complex of DNA and the histone proteins with which it associates. If the way that DNA is wrapped around the histones changes, gene expression can change as well. Chromatin remodeling is accomplished through two main mechanisms:
The first way is post translational modification of the amino acids that make up histone proteins. Histone proteins are made up of long chains of amino acids. If the amino acids that are in the chain are changed, the shape of the histone might be modified. DNA is not completely unwound during replication. It is possible, then, that the modified histones may be carried into each new copy of the DNA. Once there, these histones may act as templates, initiating the surrounding new histones to be shaped in the new manner. By altering the shape of the histones around them, these modified histones would ensure that a lineage-specific transcription program is maintained after cell division.
The second way is the addition of methyl groups to the DNA, mostly at CpG sites, to convert cytosine to 5-methylcytosine. 5-Methylcytosine performs much like a regular cytosine, pairing with a guanine in double-stranded DNA. However, some areas of the genome are methylated more heavily than others, and highly methylated areas tend to be less transcriptionally active, through a mechanism not fully understood. Methylation of cytosines can also persist from the germ line of one of the parents into the zygote, marking the chromosome as being inherited from one parent or the other (genetic imprinting).
Mechanisms of heritability of histone state are not well understood; however, much is known about the mechanism of heritability of DNA methylation state during cell division and differentiation. Heritability of methylation state depends on certain enzymes (such as DNMT1) that have a higher affinity for 5-methylcytosine than for cytosine. If this enzyme reaches a "hemimethylated" portion of DNA (where 5-methylcytosine is in only one of the two DNA strands) the enzyme will methylate the other half.
Although histone modifications occur throughout the entire sequence, the unstructured N-termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation, methylation, ubiquitylation, phosphorylation, sumoylation, ribosylation and citrullination. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 lysines of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally related to transcriptional competence.
One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because it normally has a positively charged nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge, thus loosening the DNA from the histone. When this occurs, complexes like SWI/SNF and other transcriptional factors can bind to the DNA and allow transcription to occur. This is the "cis" model of epigenetic function. In other words, changes to the histone tails have a direct effect on the DNA itself.
Another model of epigenetic function is the "trans" model. In this model, changes to the histone tails act indirectly on the DNA. For example, lysine acetylation may create a binding site for chromatin-modifying enzymes (or transcription machinery as well). This chromatin remodeler can then cause changes to the state of the chromatin. Indeed, a bromodomain ? a protein domain that specifically binds acetyl-lysine ? is found in many enzymes that help activate transcription, including the SWI/SNF complex. It may be that acetylation acts in this and the previous way to aid in transcriptional activation.
The idea that modifications act as docking modules for related factors is borne out by histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive heterochromatin). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein HP1 recruits HP1 to K9 methylated regions. One example that seems to refute this biophysical model for methylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional activation. Tri-methylation in this case would introduce a fixed positive charge on the tail.
It has been shown that the histone lysine methyltransferase (KMT) is responsible for this methylation activity in the pattern of histones H3 & H4. This enzyme utilizes a catalytically active site called the SET domain (Suppressor of variegation, Enhancer of zeste, Trithorax). The SET domain is a 130-amino acid sequence involved in modulating gene activities. This domain has been demonstrated to bind to the histone tail and causes the methylation of the histone.
Differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently from acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the histone code, although the idea that histone state can be read linearly as a digital information carrier has been largely debunked. One of the best-understood systems that orchestrates chromatin-based silencing is the SIR protein based silencing of the yeast hidden mating type loci HML and HMR.
DNA methylation frequently occurs in repeated sequences, and helps to suppress the expression and mobility of 'transposable elements': Because 5-methylcytosine can be spontaneously deaminated (replacing nitrogen by oxygen) to thymidine, CpG sites are frequently mutated and become rare in the genome, except at CpG islands where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. DNA methylation patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent DNA methyltransferases, DNMT1, DNMT3A, and DNMT3B, the loss of any of which is lethal in mice. DNMT1 is the most abundant methyltransferase in somatic cells, localizes to replication foci, has a 10?40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).
By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after DNA replication, and therefore is often referred to as the ?maintenance' methyltransferase. DNMT1 is essential for proper embryonic development, imprinting and X-inactivation. To emphasize the difference of this molecular mechanism of inheritance from the canonical Watson-Crick base-pairing mechanism of transmission of genetic information, the term 'Epigenetic templating' was introduced. Furthermore, in addition to the maintenance and transmission of methylated DNA states, the same principle could work in the maintenance and transmission of histone modifications and even cytoplasmic (structural) heritable states.
Histones H3 and H4 can also be manipulated through demethylation using histone lysine demethylase (KDM). This recently identified enzyme has a catalytically active site called the Jumonji domain (JmjC). The demethylation occurs when JmjC utilizes multiple cofactors to hydroxylate the methyl group, thereby removing it. JmjC is capable of demethylating mono-, di-, and tri-methylated substrates.
Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of states of larger chromosomal regions are suggested to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. A simplified stochastic model for this type of epigenetics is found here.
It has been suggested that chromatin-based transcriptional regulation could be mediated by the effect of small RNAs. Small interfering RNAs can modulate transcriptional gene expression via epigenetic modulation of targeted promoters.
RNA transcripts and their encoded proteins
Sometimes a gene, after being turned on, transcribes a product that (directly or indirectly) maintains the activity of that gene. For example, Hnf4 and MyoD enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factor activity of the proteins they encode. RNA signalling includes differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development. Other epigenetic changes are mediated by the production of different splice forms of RNA, or by formation of double-stranded RNA (RNAi). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are often turned on or off by signal transduction, although in some systems where syncytia or gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion. A large amount of RNA and protein is contributed to the zygote by the mother during oogenesis or via nurse cells, resulting in maternal effect phenotypes. A smaller quantity of sperm RNA is transmitted from the father, but there is recent evidence that this epigenetic information can lead to visible changes in several generations of offspring.
MicroRNAs.
MicroRNAs (miRNAs) are members of non-coding RNAs that range in size from 17 to 25 nucleotides. miRNAs regulate a large variety of biological functions in plants and animals. So far, in 2013, about 2000 miRNAs have been discovered in humans and these can be found online in an miRNA database. Each miRNA expressed in a cell may target about 100 to 200 messenger RNAs that it downregulates. Most of the downregulation of mRNAs occurs by causing the decay of the targeted mRNA, while some downregulation occurs at the level of translation into protein.
It appears that about 60% of human protein coding genes are regulated by miRNAs.[63] Many miRNAs are epigenetically regulated. About 50% of miRNA genes are associated with CpG islands, that may be repressed by epigenetic methylation. Transcription from methylated CpG islands is strongly and heritably repressed. Other miRNAs are epigenetically regulated by either histone modifications or by combined DNA methylation and histone modification.
mRNA.
In 2011, it was demonstrated that the methylation of mRNA plays a critical role in human energy homeostasis. The obesity-associated FTO gene is shown to be able to demethylate N6-methyladenosine in RNA.
sRNAs.
sRNAs are small (50?250 nucleotides), highly structured, non-coding RNA fragments found in bacteria. They control gene expression including virulence genes in pathogens and are viewed as new targets in the fight against drug-resistant bacteria. They play an important role in many biological processes, binding to mRNA and protein targets in prokaryotes. Their phylogenetic analyses, for example through sRNA?mRNA target interactions or protein binding properties, are used to build comprehensive databases. sRNA-gene maps based on their targets in microbial genomes are also constructed.
Prions.
Prions are infectious forms of proteins. In general, proteins fold into discrete units that perform distinct cellular functions, but some proteins are also capable of forming an infectious conformational state known as a prion. Although often viewed in the context of infectious disease, prions are more loosely defined by their ability to catalytically convert other native state versions of the same protein to an infectious conformational state. It is in this latter sense that they can be viewed as epigenetic agents capable of inducing a phenotypic change without a modification of the genome.
Fungal prions are considered by some to be epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. PSI+ and URE3, discovered in yeast in 1965 and 1971, are the two best studied of this type of prion. Prions can have a phenotypic effect through the sequestration of protein in aggregates, thereby reducing that protein's activity. In PSI+ cells, the loss of the Sup35 protein (which is involved in termination of translation) causes ribosomes to have a higher rate of read-through of stop codons, an effect that results in suppression of nonsense mutations in other genes. The ability of Sup35 to form prions may be a conserved trait. It could confer an adaptive advantage by giving cells the ability to switch into a PSI+ state and express dormant genetic features normally terminated by stop codon mutations.
Structural inheritance systems.
In ciliates such as Tetrahymena and Paramecium, genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.
Development.
Somatic epigenetic inheritance through epigenetic modifications, particularly through DNA methylation and chromatin remodeling, is very important in the development of multicellular eukaryotic organisms. The genome sequence is static (with some notable exceptions), but cells differentiate into many different types, which perform different functions, and respond differently to the environment and intercellular signalling. Thus, as individuals develop, morphogens activate or silence genes in an epigenetically heritable fashion, giving cells a memory. In mammals, most cells terminally differentiate, with only stem cells retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In mammals, some stem cells continue producing new differentiated cells throughout life, such as in neurogenesis, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin remodeling, it has been hypothesised that some kinds of plant cells do not use or require "cellular memories", resetting their gene expression patterns using positional information from the environment and surrounding cells to determine their fate.
Epigenetics can be divided into predetermined and probabilistic epigenesis. Predetermined epigenesis is a unidirectional movement from structural development in DNA to the functional maturation of the protein. "Predetermined" here means that development is scripted and predictable. Probabilistic epigenesis on the other hand is a bidirectional structure-function development with experiences and external molding development.
Medicine.
Epigenetics has many and varied potential medical applications as it tends to be multidimensional in nature.
Congenital genetic disease is well understood and it is clear that epigenetics can play a role, for example, in the case of Angelman syndrome and Prader-Willi syndrome. These are normal genetic diseases caused by gene deletions or inactivation of the genes, but are unusually common because individuals are essentially hemizygous because of genomic imprinting, and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.
Evolution.
Epigenetics can impact evolution when epigenetic changes are heritable. A sequestered germ line or Weismann barrier is specific to animals, and epigenetic inheritance is more common in plants and microbes. Eva Jablonka and Marion Lamb have argued that these effects may require enhancements to the standard conceptual framework of the modern evolutionary synthesis. Other evolutionary biologists have incorporated epigenetic
Inglish Site.17.
*
TO THE THRISE HO-
NOVRABLE AND EVER LY-
VING VERTVES OF SYR PHILLIP
SYDNEY KNIGHT, SYR JAMES JESUS SINGLETON, SYR CANARIS, SYR LAVRENTI BERIA ; AND TO THE
RIGHT HONORABLE AND OTHERS WHAT-
SOEVER, WHO LIVING LOVED THEM,
AND BEING DEAD GIVE THEM
THEIRE DVE.
***
In the beginning there is darkness. The screen erupts in blue, then a cascade of thick, white hexadecimal numbers and cracked language, ?UnusedStk? and ?AllocMem.? Black screen cedes to blue to white and a pair of scales appear, crossed by a sword, both images drawn in the jagged, bitmapped graphics of Windows 1.0-era clip-art?light grey and yellow on a background of light cyan. Blue text proclaims, ?God on tap!?
*
Introduction.
Yes i am getting a little Mobi-Literate(ML) by experimenting literary on my Mobile Phone. Peoplecall it Typographical Laziness(TL).
The first accidental entries for the this part of this encyclopedia.
*
This is TempleOS V2.17, the welcome screen explains, a ?Public Domain Operating System? produced by Trivial Solutions of Las Vegas, Nevada. It greets the user with a riot of 16-color, scrolling, blinking text; depending on your frame of reference, it might recall ?DESQview, the ?Commodore 64, or a host of early DOS-based graphical user interfaces. In style if not in specifics, it evokes a particular era, a time when the then-new concept of ?personal computing? necessarily meant programming and tinkering and breaking things.
*
Index.
81."Justified.
82.Epigenetics.
83.Psycholinguistics/psychology of language.
*
81."Justified And Ancient" and The KLF.
The KLF (also known as The Justified Ancients of Mu Mu, The Timelords and other names) were one of the seminal bands of the British acid house movement during the late 1980s and early 1990s.
Beginning in 1987, Bill Drummond (alias King Boy D) and Jimmy Cauty (alias Rockman Rock) released hip hop-inspired and sample-heavy records as The Justified Ancients of Mu Mu, and on one occasion (the British number one hit single "Doctorin' the Tardis") as The Timelords. The KLF released a series of international hits on their own KLF Communications record label, and became the biggest-selling singles act in the world for 1991. The duo also published a cynical book, The Manual (How to Have a Number One the Easy Way), and worked on a road movie called The White Room.
From the outset, they adopted the philosophy espoused by esoteric novel series The Illuminatus! Trilogy, gaining notoriety for various anarchic situationist manifestations, including the defacement of billboard adverts, the posting of prominent cryptic advertisements in NME magazine and the mainstream press, and highly distinctive and unusual performances on Top of the Pops. Their most notorious performance was a collaboration with Extreme Noise Terror at the February 1992 BRIT Awards, where they fired machine gun blanks into the audience and dumped a dead sheep at the aftershow party. This performance announced The KLF's departure from the music business, and in May 1992 the duo deleted their entire back catalogue.
With The KLF's profits, Drummond and Cauty established the K Foundation and sought to subvert the art world, staging an alternative art award for the worst artist of the year and burning one million pounds sterling. Drummond and Cauty remained true to their word of May 1992?the KLF Communications catalogue remains deleted in the UK, but The White Room is still being pressed in the US by Arista. They have released a small number of new tracks since then, as the K Foundation, The One World Orchestra and most recently, in 1997, as 2K.
"Justified & Ancient" is a song by British band the KLF (Bill Drummond and Jimmy Cauty) which featured on their 1991 album The White Room but with origins dating back to the duo's debut album, 1987 (What the Fuck Is Going On?).
The song is best known for its remake that was released in November 1991 as a pop-house single subtitled "Stand by The JAMs", with verses featuring the vocals of American country music singer Tammy Wynette. This version was an international hit, reaching #2 on both the UK Singles Chart, and the U.S. dance charts, #11 on the U.S. Billboard Hot 100, and hitting #1 in 18 countries.
Despite its success, "Justified & Ancient (Stand by the JAMs)" was the final release by the KLF through retail channels as well the second-to-last altogether release from the KLF (the last release being the mail-order only "3 a.m. Eternal") before Drummond and Cauty quit the music business and retired the KLF name.
"Justified And Ancient"
All bound for Mu Mu Land
All bound for Mu Mu Land
(hey)
(hey hey)
All bound for Mu Mu Land (justified)
(hey hey)
All bound for Mu Mu Land
(Bring the beat back!)_
They're Justified, and they're Ancient,
And they like to roam the land.
(just roll it from the top)
They're Justified, and they're Ancient,
I hope you understand.
(to the bridge, to the bridge, to the bridge now)
They called me up in Tennessee
They said "Tammy, stand by The Jams"
But if you don't like what they're going to do,
You better not stop them 'cause they're coming through
(bring the beat back)_
(Hey hey)
All bound for Mu Mu Land (justified)
(Hey hey)
All bound for Mu Mu Land (justified)
(Ancients of Mu Mu)_
Mu Mu Land
Mu Mu Land
All bound for Mu Mu Land_
They're Justified, and they're Ancient,
And they drive an ice cream van.
(just roll it from the top)
They're Justified and they're Ancient,
With still no master plan.
(to the bridge, to the bridge, to the bridge now)
The last train left an hour ago,
They were singing "All aboard"
All bound for Mu Mu Land,
Then someone starting screaming "Turn up the Strobe"
(bring the beat back)_
(Hey hey)
All bound for Mu Mu Land (justified)
(Hey hey)
All bound for Mu Mu Land (Ancients of Mu Mu)
(Bring the beat back)_
Justified and Ancient, Ancient and a-justified,
Rocking to the rhythm in their ice cream van
with the plan and the key to
enter into Mu Mu
Vibes from the tribes of the Jams_
I know where the beat is at,
'cos I know what time it is
Bring home a dime,
Make mine a "99"_
New style, meanwhile, always on a mission while
Fishing in the rivers of life
Fishing in the rivers of life (hoi)
Fishing in the rivers of life (hoi)
Fishing in the rivers
Fishing in the rivers
Fishing in the rivers of life (hoi)_
Voo-va-voolie
Za-shi-va-zom
Voo-va-voolie
(Bring the beat back)_
(Hey hey)
All bound for Mu Mu Land (justified)
(Hey hey)
All bound for Mu Mu Land (Ancients of Mu Mu)_
They have travelled the world
With the ice cream van
Their voyage, the bottom of time
They have entered the place
with the Mu Mu mate
And their children so pride
Mine as a "99"
(Bring the beat back)_
Mu Mu Land (Ancients of Mu Mu)
Mu Mu Land (Ancients of Mu Mu)
All bound for Mu Mu Land_
Mu Mu Land (Ancients of Mu Mu)
Mu Mu Land (Ancients of Mu Mu)
All bound for Mu Mu Land_
Mu Mu Land
Mu Mu Land
All bound for Mu Mu Land_
The title "Justified & Ancient" refers to the KLF's pseudonym and earlier incarnation, "The Justified Ancients of Mu Mu" (The JAMs). The JAMs took their name from a fictional subversive cult from the 1970s conspiratorial novels The Illuminatus! Trilogy. Just as the fictional JAMs made it their remit to propagate chaos and confusion, so too did the real JAMs and the KLF. Their attempts to subvert the music industry and other establishments were frequent, unconcealed and controversial. The song "Justified & Ancient" is a statement of identity and rebellious intent. Moreover, it deliberately understates this intent. In contrast to the provocative and abrasive lyrics of the JAMs' album 1987 (What the Fuck Is Going On?), on which "Justified & Ancient" first appeared, the song has a soft and innocuous tune, and quaint lyrics:
"We don't want to upset the apple-cart (Kallisti), and we don't want to cause any harm, but if you don't like what we're going to do, you'd better not stop us 'cause we're coming through."
The words and music of "Justified & Ancient" feature several times in the work of The KLF and The JAMs, including their first album and their last full-release single.
The melody and one repeated lyrical verse of the song first appeared as part of "Hey Hey We Are Not The Monkees" from The JAMs' debut album, 1987: What The Fuck Is Going On?. All of the album's most prominent characteristics are notably absent in this part of "Hey Hey...", which has female vocals (as opposed to the rapping of The JAMs' Scottish co-founder Bill Drummond), inoffensive lyrics, and it is free from plagiarised samples of other artists' recordings. Also in contrast, "Hey Hey" itself begins with a minute's worth of typical human sexual intercourse noises, arranged as a rhythm. It progresses into a cryptic and bleak spoken verse from Drummond and descends into a cacophony of samples from "The Monkees Theme". An abrupt cut takes the track into the gentle "Justified & Ancient" vocal line, which is syncopated similarly to African music and is at first a cappella.
In 1990, the recording re-appeared on The KLF's ambient album, Chill Out, in a part of the composition titled "Justified & Ancient Seems a Long Time Ago". This time the song provides a complement rather than a contrast to the mood of the album, which is passive and contains various authentic ethnic sounds.
In March 1991, a full song called "Justified & Ancient" appeared on The KLF's album The White Room. Sung by Black Steel, the song begins and ends the album. This version retains the lyrics and melody, adds an additional verse, and full song structure and instrumentation is present, in an arrangement akin to a lullaby. Where the song starts the album, it is interrupted at the point "...they're coming through" by urgent "Mu Mu!" samples and blazing machine guns that open the house track "What Time Is Love?". At the end of the mellower second half of the album, the song is presented in its entirety.
In 1986, Bill Drummond was an established figure within the British music industry, having co-founded Zoo Records, played guitar in the Liverpool band Big in Japan, and worked as manager of Echo & the Bunnymen and The Teardrop Explodes. On 21 July of that year, he resigned from his position as an A&R man at record label WEA, citing that he was nearly 33? years old (33? revolutions per minute being significant to Drummond as the speed at which a vinyl LP revolves), and that it was "time for a revolution in my life. There is a mountain to climb the hard way, and I want to see the world from the top". He released a well-received solo LP, The Man, judged by reviewers as "tastefully understated," a "touching if idiosyncratic biographical statement" encapsulating "his bizarrely sage ruminations", and "a work of humble genius: the best kind".
Artist and musician Jimmy Cauty was, in 1986, the guitarist in the commercially unsuccessful three-piece Brilliant[10]?an act that Drummond had signed to WEA Records and managed. Cauty and Drummond shared an interest in the esoteric conspiracy novels The Illuminatus! Trilogy, and, in particular, their theme of Discordianism, a form of post-modern anarchism. As an art student in Liverpool, Drummond had been involved with the set design for the first stage production of The Illuminatus! Trilogy, a 12-hour performance which opened in Liverpool on 23 November 1976.
Re-reading Illuminatus! in late 1986, and influenced by hip-hop, Drummond felt inspired to react against what he perceived to be the stagnant soundscape of popular music. Recalling that moment in a later radio interview, Drummond said that the plan came to him in an instant: he would form a hip-hop band with former colleague Jimmy Cauty, and they would be called The Justified Ancients of Mu Mu.
It was New Year's Day ... 1987. I was at home with my parents, I was going for a walk in the morning, it was, like, bright blue sky, and I thought "I'm going to make a hip-hop record. Who can I make a hip-hop record with?". I wasn't brave enough to go and do it myself, 'cause, although I can play the guitar, and I can knock out a few things on the piano, I knew nothing, personally, about the technology. And, I thought, I knew [Jimmy], I knew he was a like spirit, we share similar tastes and backgrounds in music and things. So I phoned him up that day and said "Let's form a band called The Justified Ancients of Mu-Mu". And he knew exactly, to coin a phrase, "where I was coming from". And within a week we had recorded our first single which was called "All You Need Is Love".?
The Justified Ancients of Mu Mu
Early in 1987, Drummond and Cauty's collaborations began. They assumed alter egos?King Boy D and Rockman Rock respectively?and they adopted the name The Justified Ancients of Mu Mu (The JAMs), after the fictional conspiratorial group "The Justified Ancients of Mummu" from The Illuminatus! Trilogy. In those novels, the JAMs are what the Illuminati (a political organisation which seeks to impose order and control upon society) call a group of Discordians who have infiltrated the Illuminati in order to feed them false information. As The Justified Ancients of Mu Mu, Drummond and Cauty chose to interpret the principles of the fictional JAMs in the context of music production in the corporate music world.[citation needed] Shrouded in the mystique provided by their disguised identities and the cultish Illuminatus!, they mirrored the Discordians' gleeful political tactics of causing chaos and confusion by bringing a direct, humorous but nevertheless revolutionary approach to making records, often attracting attention in unconventional ways. The JAMs' primary instrument was the digital sampler with which they would plagiarise the history of popular music, cutting chunks from existing works and pasting them into new contexts, underpinned by rudimentary beatbox rhythms and overlaid with Drummond's raps, of social commentary, esoteric metaphors and mockery. (This technique is rather similar to that used by The Residents on their album Meet the Residents).
The JAMs' debut studio single "All You Need Is Love" dealt with the media coverage given to AIDS, sampling heavily from The Beatles' "All You Need Is Love" and Samantha Fox's "Touch Me (I Want Your Body)". Although it was declined by distributors fearful of prosecution, and threatened with lawsuits, copies of the one-sided white label 12" were sent to the music press; it received positive reviews and was made "single of the week" in Sounds. A later piece in the same magazine called The JAMs "the hottest, most exhilarating band this year.... It's hard to understand what it feels like to come across something you believe to be totally new; I have never been so wholeheartedly convinced that a band are so good and exciting."
The JAMs re-edited and re-released "All You Need Is Love" in May 1987, removing or doctoring the most antagonistic samples; lyrics from the song appeared as promotional graffiti, defacing selected billboards. The re-release rewarded The JAMs not just with further praise (including NME´s "single of the week") but also with the funds necessary to record their debut album. The album, 1987 (What the Fuck Is Going On?), was released in June 1987. Included was a song called "The Queen and I", which sampled large portions of the ABBA single "Dancing Queen". The recording came to the attention of ABBA's management and, after a legal showdown with ABBA and the Mechanical-Copyright Protection Society, the 1987 album was forcibly withdrawn from sale. Drummond and Cauty travelled to Sweden in hope of meeting ABBA and coming to some agreement, taking an NME journalist and photographer with them, along with most of the remaining copies of the LP. They failed to meet ABBA, so disposed of the copies by burning most of them in a field and throwing the rest overboard on the North Sea ferry trip home. In a December 1987 interview, Cauty maintained that they "felt that what [they]'d done was artistically justified."
Two new singles followed 1987, on The JAMs' "KLF Communications" independent record label. Both reflected a shift towards house rhythms. According to NME, The JAMs' choice of samples for the first of these, "Whitney Joins The JAMs" saw them leaving behind their strategy of "collision course" to "move straight onto the art of super selective theft". The song uses samples of the Mission: Impossible and Shaft themes alongside Whitney Houston's "I Wanna Dance With Somebody". Ironically, Drummond has claimed that The KLF were later offered the job of producing or remixing a new Whitney Houston album as an inducement from her record label boss (Clive Davis of Arista Records) to sign with them. Drummond turned the job down, but nonetheless The KLF signed with Arista as their American distributors. The second single in this sequence?Drummond and Cauty's third and final single of 1987?was "Down Town", a dance record built around a gospel choir and "Downtown" by 1960s star Petula Clark. These early works were later collected on the compilation album Shag Times.
A second album, Who Killed The JAMs?, was released in early 1988. Who Killed The JAMs? was a rather less haphazard affair than 1987, earning the duo at least one five-star review (from Sounds Magazine, who called it "a masterpiece of pathos".)
The Timelords.
In 1988, Drummond and Cauty became "Time Boy" and "Lord Rock", and released a 'novelty' pop single, "Doctorin' the Tardis" as The Timelords. The song is predominantly a mash-up of the Doctor Who theme music, "Block Buster!" by The Sweet and Gary Glitter's "Rock and Roll (Part Two)", with sparse vocals inspired by The Daleks and Harry Enfield's "Loadsamoney" character. "Doctorin' the Tardis" reached number one in the UK Singles Chart on 12 June, and charted highly in Australia and New Zealand.
Also credited on the record was "Ford Timelord", Cauty's 1968 Ford Galaxie American police car (claimed to have been used in the film Superman IV filmed in the UK). Drummond and Cauty declared that the car had spoken to them, giving its name as Ford Timelord, and advising the duo to become "The Timelords".
Drummond and Cauty would later portray the song as the result of a deliberate effort to write a number one hit single. However, in interviews with Snub TV and BBC Radio 1, Drummond said that the truth was that they had intended to make a house record using the Dr Who theme. After Cauty had laid down a basic track, Drummond observed that their house idea wasn't working and what they actually had was a Glitter beat. Sensing the opportunity to make a commercial pop record they abandoned all notions of underground credibility and went instead for the lowest common denominator. According to the British music press, the result was "rancid", "pure, unadulterated agony" and "excruciating" and?in something of a backhanded compliment from the normally supportive Sounds Magazine?"a record so noxious that a top ten place can be its only destiny". They were right: the record went on to sell over one million copies. A single of The Timelords' remixes of the song was released: "Gary Joins The JAMs" featured original vocal contributions from Glitter himself, who also appeared on Top of the Pops to promote the song with The Timelords.
The Timelords released one other product, a 1989 book called The Manual (How to Have a Number One the Easy Way), a tongue-in-cheek but nonetheless insightful step-by-step guide to achieving a number one hit single with little money or talent.
The KLF.
By the time the JAMs' single "Whitney Joins The JAMs" was released in September 1987, their record label had been renamed "KLF Communications" (from the earlier "The Sound of Mu(sic)"). However, the duo's first release as The KLF was not until March 1988, with the single "Burn the Bastards"/"Burn the Beat" (KLF 002). Although the Justified Ancients of Mu Mu name was not yet retired, most future Drummond and Cauty releases would go under the name "The KLF".
The name change accompanied a change in Drummond and Cauty's musical direction. Said Drummond (as 'King Boy D') in January 1988, "We might put out a couple of 12" records under the name The K.L.F., these will be rap free just pure dance music, so don't expect to see them reviewed in the music papers". King Boy D also claimed that he and Rockman Rock were "pissed off at [them]selves" for letting "people expect us to lead some sort of crusade for sampling". In 1990 he recalled that "We wanted to make [as The KLF] something that was ... pure dance music, without any reference points, without any nod to the history of rock and roll. It was the type of music that by early '87 was really exciting me ... [although] we weren't able to get our first KLF records out until late '88".
The 12" records subsequently released in 1988 and 1989 by The KLF were indeed rap free and house-oriented; remixes of some of The JAMs tracks, and new singles, the largely instrumental acid house anthems "What Time Is Love?" and "3 a.m. Eternal", the first incarnations of later international chart successes. The KLF described these new tracks as "Pure Trance". In 1989, The KLF appeared at the Helter Skelter rave in Oxfordshire. "They wooed the crowd", wrote Scotland on Sunday some years later, "by pelting them with... £1,000 worth of Scottish pound notes which each bore the message 'Children we love you'".
Also in 1989, The KLF embarked upon the creation of a road movie and soundtrack album, both titled The White Room, funded by the profits of "Doctorin' The Tardis". Neither the film nor its soundtrack were formally released, although bootleg copies of both exist. The soundtrack album contained pop-house versions of some of the "pure trance" singles, as well as new songs, most of which would appear (albeit in radically reworked form) on the version of the album which was eventually released to mainstream success. A single from the original album was released, however: "Kylie Said to Jason", an electropop record featuring references to Todd Terry, Rolf Harris, Skippy the Bush Kangaroo and BBC comedy programme The Good Life. In reference to that song, Drummond and Cauty noted that they had worn "Pet Shop Boys infatuations brazenly on [their] sleeves".
The film project was fraught with difficulties and setbacks, including dwindling funds. "Kylie Said to Jason", which Drummond and Cauty were hoping could "rescue them from the jaws of bankruptcy", flopped commercially, failing even to make the UK top 100. In consequence, The White Room film project was put on hold, and The KLF abandoned the musical direction of the soundtrack and single. Meanwhile, "What Time Is Love?" was generating acclaim within the underground clubs of continental Europe; according to KLF Communications, "The KLF were being feted by all the 'right' DJs". This prompted Drummond and Cauty to pursue the acid house tone of their Pure Trance series. A further Pure Trance release, "Last Train to Trancentral", followed. At this time, Cauty had co-founded The Orb as an ambient side-project with Alex Paterson. Cauty and Paterson DJ-ed at the monthly "Land Of Oz" house night in London, and The KLF's seminal 1990 "ambient house" LP Chill Out was born partly from these sessions. The ambient album Space and The KLF's ambient video Waiting were also released in 1990, as was a heavier, more industrial sounding dance track, "It's Grim Up North", under The JAMs' moniker.
In 1990 The KLF launched a series of singles with an upbeat pop-house sound which they dubbed "Stadium House". Songs from The White Room soundtrack were re-recorded with.....
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82.Epigenetics.
In biology, epigenetics is the study of cellular and physiological trait variations that are not caused by changes in the DNA sequence; epigenetics describes the study of dynamic alterations in the transcriptional potential of a cell. These alterations may or may not be heritable, although the use of the term epigenetic to describe processes that are not heritable is controversial. Unlike genetics based on changes to the DNA sequence (the genotype), the changes in gene expression or cellular phenotype of epigenetics have other causes, thus use of the term epi- (Greek: ???- over, outside of, around) -genetics.
The term also refers to the changes themselves: functionally relevant changes to the genome that do not involve a change in the nucleotide sequence. Examples of mechanisms that produce such changes are DNA methylation and histone modification, each of which alters how genes are expressed without altering the underlying DNA sequence. Gene expression can be controlled through the action of repressor proteins that attach to silencer regions of the DNA. These epigenetic changes may last through cell divisions for the duration of the cell's life, and may also last for multiple generations even though they do not involve changes in the underlying DNA sequence of the organism; instead, non-genetic factors cause the organism's genes to behave (or "express themselves") differently.
One example of an epigenetic change in eukaryotic biology is the process of cellular differentiation. During morphogenesis, totipotent stem cells become the various pluripotent cell lines of the embryo, which in turn become fully differentiated cells. In other words, as a single fertilized egg cell ? the zygote ? continues to divide, the resulting daughter cells change into all the different cell types in an organism, including neurons, muscle cells, epithelium, endothelium of blood vessels, etc., by activating some genes while inhibiting the expression of others.
Historical usage.
Epigenetics (as in "epigenetic landscape") was coined by C. H. Waddington in 1942 as a portmanteau of the words epigenesis and genetics. Epigenesis is an old word that has more recently been used (see preformationism for historical background) to describe the differentiation of cells from their initial totipotent state in embryonic development. When Waddington coined the term the physical nature of genes and their role in heredity was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype; he used the phrase "epigenetic landscape" as a metaphor for biological development. Waddington held that cell fates were established in development much like a marble rolls down to the point of lowest local elevation. Waddington suggested visualising increasing irreversibility of cell type differentiation as ridges rising between the valleys where the marbles (cells) are travelling. In recent times Waddington's notion of the epigenetic landscape has been rigorously formalized in the context of the systems dynamics state approach to the study of cell-fate.
The term "epigenetics" has also been used in developmental psychology to describe psychological development as the result of an ongoing, bi-directional interchange between heredity and the environment. Interactivist ideas of development have been discussed in various forms and under various names throughout the 19th and 20th centuries. An early version was proposed, among the founding statements in embryology, by Karl Ernst von Baer and popularized by Ernst Haeckel. A radical epigenetic view (physiological epigenesis) was developed by Paul Wintrebert. Another variation, probabilistic epigenesis, was presented by Gilbert Gottlieb in 2003. This view encompasses all of the possible developing factors on an organism and how they not only influence the organism and each other but how the organism also influences its own development.
The developmental psychologist Erik Erikson used the term epigenetic principle in his book Identity: Youth and Crisis (1968), and used it to encompass the notion that we develop through an unfolding of our personality in predetermined stages, and that our environment and surrounding culture influence how we progress through these stages. This biological unfolding in relation to our socio-cultural settings is done in stages of psychosocial development, where "progress through each stage is in part determined by our success, or lack of success, in all the previous stages."
Contemporary usage.
Epigenetic mechanisms.
Robin Holliday defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms." Thus epigenetic can be used to describe anything other than DNA sequence that influences the development of an organism.
The more recent usage of the word in science has a stricter definition. It is, as defined by Arthur Riggs and colleagues, "the study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence." The Greek prefix epi- in epigenetics implies features that are "on top of" or "in addition to" genetics; thus epigenetic traits exist on top of or in addition to the traditional molecular basis for inheritance.
The term "epigenetics", however, has been used to describe processes which have not been demonstrated to be heritable such as histone modification; there are therefore attempts to redefine it in broader terms that would avoid the constraints of requiring heritability. For example, Sir Adrian Bird defined epigenetics as "the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states." This definition would be inclusive of transient modifications associated with DNA repair or cell-cycle phases as well as stable changes maintained across multiple cell generations, but exclude others such as templating of membrane architecture and prions unless they impinge on chromosome function. Such redefinitions however are not universally accepted and are still subject to dispute. The NIH "Roadmap Epigenomics Project," ongoing as of 2013, uses the following definition: "...For purposes of this program, epigenetics refers to both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable."
In 2008, a consensus definition of the epigenetic trait, "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence", was made at a Cold Spring Harbor meeting.
The similarity of the word to "genetics" has generated many parallel usages. The "epigenome" is a parallel to the word "genome", referring to the overall epigenetic state of a cell, and epigenomics refers to more global analyses of epigenetic changes across the entire genome. The phrase "genetic code" has also been adapted?the "epigenetic code" has been used to describe the set of epigenetic features that create different phenotypes in different cells. Taken to its extreme, the "epigenetic code" could represent the total state of the cell, with the position of each molecule accounted for in an epigenomic map, a diagrammatic representation of the gene expression, DNA methylation and histone modification status of a particular genomic region. More typically, the term is used in reference to systematic efforts to measure specific, relevant forms of epigenetic information such as the histone code or DNA methylation patterns.
Epigenetic changes can modify the activation of certain genes, but not the sequence of DNA. Additionally, the chromatin proteins associated with DNA may be activated or silenced. This is why the differentiated cells in a multicellular organism express only the genes that are necessary for their own activity. Epigenetic changes are preserved when cells divide. Most epigenetic changes only occur within the course of one individual organism's lifetime, but, if gene inactivation occurs in a sperm or egg cell that results in fertilization, then some epigenetic changes can be transferred to the next generation. This raises the question of whether or not epigenetic changes in an organism can alter the basic structure of its DNA (see Evolution, below), a form of Lamarckism.
Specific epigenetic processes include paramutation, bookmarking, imprinting, gene silencing, X chromosome inactivation, position effect, reprogramming, transvection, maternal effects, the progress of carcinogenesis, many effects of teratogens, regulation of histone modifications and heterochromatin, and technical limitations affecting parthenogenesis and cloning.
DNA damage can also cause epigenetic changes. DNA damages are very frequent, occurring on average about 10,000 times a day per cell of the human body (see DNA damage (naturally occurring)). These damages are largely repaired, but at the site of a DNA repair, epigenetic changes can remain. In particular, a double strand break in DNA can initiate unprogrammed epigenetic gene silencing both by causing DNA methylation as well as by promoting silencing types of histone modifications (chromatin remodeling) (see next section). In addition, the enzyme Parp1 (poly(ADP)-ribose polymerase) and its product poly(ADP)-ribose (PAR) accumulate at sites of DNA damage as part of a repair process. This accumulation, in turn, directs recruitment and activation of the chromatin remodeling protein ALC1 that can cause nucleosome remodeling. Nucleosome remodeling has been found to cause, for instance, epigenetic silencing of DNA repair gene MLH1. DNA damaging chemicals, such as benzene, hydroquinone, styrene, carbon tetrachloride and trichloroethylene, cause considerable hypomethylation of DNA, some through the activation of oxidative stress pathways.
Foods are known to alter the epigenetics of rats on different diets. Some food components epigenetically increase the levels of DNA repair enzymes such as MGMT and MLH1 and p53. Other food components can reduce DNA damage, such as soy isoflavones and bilberry anthocyanins.
Epigenetic research uses a wide range of molecular biologic techniques to further our understanding of epigenetic phenomena, including chromatin immunoprecipitation (together with its large-scale variants ChIP-on-chip and ChIP-Seq), fluorescent in situ hybridization, methylation-sensitive restriction enzymes, DNA adenine methyltransferase identification (DamID) and bisulfite sequencing. Furthermore, the use of bioinformatic methods is playing an increasing role (computational epigenetics).
Computer simulations and molecular dynamics approaches revealed the atomistic motions associated with the molecular recognition of the histone tail through an allosteric mechanism.
Several types of epigenetic inheritance systems may play a role in what has become known as cell memory, note however that not all of these are universally accepted to be examples of epigenetics.
DNA methylation and chromatin remodeling.
Because DNA methylation and chromatin remodeling play such a central role in many types of epigenic inheritance, the word "epigenetics" is sometimes used as a synonym for these processes. However, this can be misleading. Chromatin remodeling is not always inherited, and not all epigenetic inheritance involves chromatin remodeling.
DNA associates with histone proteins to form chromatin.
Because the phenotype of a cell or individual is affected by which of its genes are transcribed, heritable transcription states can give rise to epigenetic effects. There are several layers of regulation of gene expression. One way that genes are regulated is through the remodeling of chromatin. Chromatin is the complex of DNA and the histone proteins with which it associates. If the way that DNA is wrapped around the histones changes, gene expression can change as well. Chromatin remodeling is accomplished through two main mechanisms:
The first way is post translational modification of the amino acids that make up histone proteins. Histone proteins are made up of long chains of amino acids. If the amino acids that are in the chain are changed, the shape of the histone might be modified. DNA is not completely unwound during replication. It is possible, then, that the modified histones may be carried into each new copy of the DNA. Once there, these histones may act as templates, initiating the surrounding new histones to be shaped in the new manner. By altering the shape of the histones around them, these modified histones would ensure that a lineage-specific transcription program is maintained after cell division.
The second way is the addition of methyl groups to the DNA, mostly at CpG sites, to convert cytosine to 5-methylcytosine. 5-Methylcytosine performs much like a regular cytosine, pairing with a guanine in double-stranded DNA. However, some areas of the genome are methylated more heavily than others, and highly methylated areas tend to be less transcriptionally active, through a mechanism not fully understood. Methylation of cytosines can also persist from the germ line of one of the parents into the zygote, marking the chromosome as being inherited from one parent or the other (genetic imprinting).
Mechanisms of heritability of histone state are not well understood; however, much is known about the mechanism of heritability of DNA methylation state during cell division and differentiation. Heritability of methylation state depends on certain enzymes (such as DNMT1) that have a higher affinity for 5-methylcytosine than for cytosine. If this enzyme reaches a "hemimethylated" portion of DNA (where 5-methylcytosine is in only one of the two DNA strands) the enzyme will methylate the other half.
Although histone modifications occur throughout the entire sequence, the unstructured N-termini of histones (called histone tails) are particularly highly modified. These modifications include acetylation, methylation, ubiquitylation, phosphorylation, sumoylation, ribosylation and citrullination. Acetylation is the most highly studied of these modifications. For example, acetylation of the K14 and K9 lysines of the tail of histone H3 by histone acetyltransferase enzymes (HATs) is generally related to transcriptional competence.
One mode of thinking is that this tendency of acetylation to be associated with "active" transcription is biophysical in nature. Because it normally has a positively charged nitrogen at its end, lysine can bind the negatively charged phosphates of the DNA backbone. The acetylation event converts the positively charged amine group on the side chain into a neutral amide linkage. This removes the positive charge, thus loosening the DNA from the histone. When this occurs, complexes like SWI/SNF and other transcriptional factors can bind to the DNA and allow transcription to occur. This is the "cis" model of epigenetic function. In other words, changes to the histone tails have a direct effect on the DNA itself.
Another model of epigenetic function is the "trans" model. In this model, changes to the histone tails act indirectly on the DNA. For example, lysine acetylation may create a binding site for chromatin-modifying enzymes (or transcription machinery as well). This chromatin remodeler can then cause changes to the state of the chromatin. Indeed, a bromodomain ? a protein domain that specifically binds acetyl-lysine ? is found in many enzymes that help activate transcription, including the SWI/SNF complex. It may be that acetylation acts in this and the previous way to aid in transcriptional activation.
The idea that modifications act as docking modules for related factors is borne out by histone methylation as well. Methylation of lysine 9 of histone H3 has long been associated with constitutively transcriptionally silent chromatin (constitutive heterochromatin). It has been determined that a chromodomain (a domain that specifically binds methyl-lysine) in the transcriptionally repressive protein HP1 recruits HP1 to K9 methylated regions. One example that seems to refute this biophysical model for methylation is that tri-methylation of histone H3 at lysine 4 is strongly associated with (and required for full) transcriptional activation. Tri-methylation in this case would introduce a fixed positive charge on the tail.
It has been shown that the histone lysine methyltransferase (KMT) is responsible for this methylation activity in the pattern of histones H3 & H4. This enzyme utilizes a catalytically active site called the SET domain (Suppressor of variegation, Enhancer of zeste, Trithorax). The SET domain is a 130-amino acid sequence involved in modulating gene activities. This domain has been demonstrated to bind to the histone tail and causes the methylation of the histone.
Differing histone modifications are likely to function in differing ways; acetylation at one position is likely to function differently from acetylation at another position. Also, multiple modifications may occur at the same time, and these modifications may work together to change the behavior of the nucleosome. The idea that multiple dynamic modifications regulate gene transcription in a systematic and reproducible way is called the histone code, although the idea that histone state can be read linearly as a digital information carrier has been largely debunked. One of the best-understood systems that orchestrates chromatin-based silencing is the SIR protein based silencing of the yeast hidden mating type loci HML and HMR.
DNA methylation frequently occurs in repeated sequences, and helps to suppress the expression and mobility of 'transposable elements': Because 5-methylcytosine can be spontaneously deaminated (replacing nitrogen by oxygen) to thymidine, CpG sites are frequently mutated and become rare in the genome, except at CpG islands where they remain unmethylated. Epigenetic changes of this type thus have the potential to direct increased frequencies of permanent genetic mutation. DNA methylation patterns are known to be established and modified in response to environmental factors by a complex interplay of at least three independent DNA methyltransferases, DNMT1, DNMT3A, and DNMT3B, the loss of any of which is lethal in mice. DNMT1 is the most abundant methyltransferase in somatic cells, localizes to replication foci, has a 10?40-fold preference for hemimethylated DNA and interacts with the proliferating cell nuclear antigen (PCNA).
By preferentially modifying hemimethylated DNA, DNMT1 transfers patterns of methylation to a newly synthesized strand after DNA replication, and therefore is often referred to as the ?maintenance' methyltransferase. DNMT1 is essential for proper embryonic development, imprinting and X-inactivation. To emphasize the difference of this molecular mechanism of inheritance from the canonical Watson-Crick base-pairing mechanism of transmission of genetic information, the term 'Epigenetic templating' was introduced. Furthermore, in addition to the maintenance and transmission of methylated DNA states, the same principle could work in the maintenance and transmission of histone modifications and even cytoplasmic (structural) heritable states.
Histones H3 and H4 can also be manipulated through demethylation using histone lysine demethylase (KDM). This recently identified enzyme has a catalytically active site called the Jumonji domain (JmjC). The demethylation occurs when JmjC utilizes multiple cofactors to hydroxylate the methyl group, thereby removing it. JmjC is capable of demethylating mono-, di-, and tri-methylated substrates.
Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of states of larger chromosomal regions are suggested to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. A simplified stochastic model for this type of epigenetics is found here.
It has been suggested that chromatin-based transcriptional regulation could be mediated by the effect of small RNAs. Small interfering RNAs can modulate transcriptional gene expression via epigenetic modulation of targeted promoters.
RNA transcripts and their encoded proteins
Sometimes a gene, after being turned on, transcribes a product that (directly or indirectly) maintains the activity of that gene. For example, Hnf4 and MyoD enhance the transcription of many liver- and muscle-specific genes, respectively, including their own, through the transcription factor activity of the proteins they encode. RNA signalling includes differential recruitment of a hierarchy of generic chromatin modifying complexes and DNA methyltransferases to specific loci by RNAs during differentiation and development. Other epigenetic changes are mediated by the production of different splice forms of RNA, or by formation of double-stranded RNA (RNAi). Descendants of the cell in which the gene was turned on will inherit this activity, even if the original stimulus for gene-activation is no longer present. These genes are often turned on or off by signal transduction, although in some systems where syncytia or gap junctions are important, RNA may spread directly to other cells or nuclei by diffusion. A large amount of RNA and protein is contributed to the zygote by the mother during oogenesis or via nurse cells, resulting in maternal effect phenotypes. A smaller quantity of sperm RNA is transmitted from the father, but there is recent evidence that this epigenetic information can lead to visible changes in several generations of offspring.
MicroRNAs.
MicroRNAs (miRNAs) are members of non-coding RNAs that range in size from 17 to 25 nucleotides. miRNAs regulate a large variety of biological functions in plants and animals. So far, in 2013, about 2000 miRNAs have been discovered in humans and these can be found online in an miRNA database. Each miRNA expressed in a cell may target about 100 to 200 messenger RNAs that it downregulates. Most of the downregulation of mRNAs occurs by causing the decay of the targeted mRNA, while some downregulation occurs at the level of translation into protein.
It appears that about 60% of human protein coding genes are regulated by miRNAs.[63] Many miRNAs are epigenetically regulated. About 50% of miRNA genes are associated with CpG islands, that may be repressed by epigenetic methylation. Transcription from methylated CpG islands is strongly and heritably repressed. Other miRNAs are epigenetically regulated by either histone modifications or by combined DNA methylation and histone modification.
mRNA.
In 2011, it was demonstrated that the methylation of mRNA plays a critical role in human energy homeostasis. The obesity-associated FTO gene is shown to be able to demethylate N6-methyladenosine in RNA.
sRNAs.
sRNAs are small (50?250 nucleotides), highly structured, non-coding RNA fragments found in bacteria. They control gene expression including virulence genes in pathogens and are viewed as new targets in the fight against drug-resistant bacteria. They play an important role in many biological processes, binding to mRNA and protein targets in prokaryotes. Their phylogenetic analyses, for example through sRNA?mRNA target interactions or protein binding properties, are used to build comprehensive databases. sRNA-gene maps based on their targets in microbial genomes are also constructed.
Prions.
Prions are infectious forms of proteins. In general, proteins fold into discrete units that perform distinct cellular functions, but some proteins are also capable of forming an infectious conformational state known as a prion. Although often viewed in the context of infectious disease, prions are more loosely defined by their ability to catalytically convert other native state versions of the same protein to an infectious conformational state. It is in this latter sense that they can be viewed as epigenetic agents capable of inducing a phenotypic change without a modification of the genome.
Fungal prions are considered by some to be epigenetic because the infectious phenotype caused by the prion can be inherited without modification of the genome. PSI+ and URE3, discovered in yeast in 1965 and 1971, are the two best studied of this type of prion. Prions can have a phenotypic effect through the sequestration of protein in aggregates, thereby reducing that protein's activity. In PSI+ cells, the loss of the Sup35 protein (which is involved in termination of translation) causes ribosomes to have a higher rate of read-through of stop codons, an effect that results in suppression of nonsense mutations in other genes. The ability of Sup35 to form prions may be a conserved trait. It could confer an adaptive advantage by giving cells the ability to switch into a PSI+ state and express dormant genetic features normally terminated by stop codon mutations.
Structural inheritance systems.
In ciliates such as Tetrahymena and Paramecium, genetically identical cells show heritable differences in the patterns of ciliary rows on their cell surface. Experimentally altered patterns can be transmitted to daughter cells. It seems existing structures act as templates for new structures. The mechanisms of such inheritance are unclear, but reasons exist to assume that multicellular organisms also use existing cell structures to assemble new ones.
Development.
Somatic epigenetic inheritance through epigenetic modifications, particularly through DNA methylation and chromatin remodeling, is very important in the development of multicellular eukaryotic organisms. The genome sequence is static (with some notable exceptions), but cells differentiate into many different types, which perform different functions, and respond differently to the environment and intercellular signalling. Thus, as individuals develop, morphogens activate or silence genes in an epigenetically heritable fashion, giving cells a memory. In mammals, most cells terminally differentiate, with only stem cells retaining the ability to differentiate into several cell types ("totipotency" and "multipotency"). In mammals, some stem cells continue producing new differentiated cells throughout life, such as in neurogenesis, but mammals are not able to respond to loss of some tissues, for example, the inability to regenerate limbs, which some other animals are capable of. Unlike animals, plant cells do not terminally differentiate, remaining totipotent with the ability to give rise to a new individual plant. While plants do utilise many of the same epigenetic mechanisms as animals, such as chromatin remodeling, it has been hypothesised that some kinds of plant cells do not use or require "cellular memories", resetting their gene expression patterns using positional information from the environment and surrounding cells to determine their fate.
Epigenetics can be divided into predetermined and probabilistic epigenesis. Predetermined epigenesis is a unidirectional movement from structural development in DNA to the functional maturation of the protein. "Predetermined" here means that development is scripted and predictable. Probabilistic epigenesis on the other hand is a bidirectional structure-function development with experiences and external molding development.
Medicine.
Epigenetics has many and varied potential medical applications as it tends to be multidimensional in nature.
Congenital genetic disease is well understood and it is clear that epigenetics can play a role, for example, in the case of Angelman syndrome and Prader-Willi syndrome. These are normal genetic diseases caused by gene deletions or inactivation of the genes, but are unusually common because individuals are essentially hemizygous because of genomic imprinting, and therefore a single gene knock out is sufficient to cause the disease, where most cases would require both copies to be knocked out.
Evolution.
Epigenetics can impact evolution when epigenetic changes are heritable. A sequestered germ line or Weismann barrier is specific to animals, and epigenetic inheritance is more common in plants and microbes. Eva Jablonka and Marion Lamb have argued that these effects may require enhancements to the standard conceptual framework of the modern evolutionary synthesis. Other evolutionary biologists have incorporated epigenetic
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