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Epigenetics - Wikipedia, the free encyclopedia. Epigenetics studies genetic effects not encoded in the DNA sequence of an organism, hence the prefix epi- (Greek: . Epigenetics can affect 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, Marion. Epigenetics Jorg Tost Pdf995Inactivation of the DNA-Repair Gene MGMT and the Clinical Response of Gliomas to Alkylating Agents. Manel Esteller, M.D., Ph.D., Jesus Garcia-Foncillas, M.D., Ph.D., Esther Andion, B.Sc., Steven N. 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. During morphogenesis, totipotentstem cells become the various pluripotentcell lines of the embryo, which in turn become fully differentiated cells. In other words, as a single fertilized egg cell . Waddington in 1. 94. Valentin Haecker\'s \'phenogenetics\' (P. Waddington held that cell fates were established in development much like a marble rolls down to the point of lowest local elevation. 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 2.
This biological unfolding in relation to our socio- cultural settings is done in stages of psychosocial development, where . It is, as defined by Arthur Riggs and colleagues, . For example, Sir Adrian Bird defined epigenetics as . Such redefinitions however are not universally accepted and are still subject to dispute. Taken to its extreme, the . 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. Molecular basis. The microstructure (not code) of DNA itself or the associated chromatin proteins may be modified, causing activation or silencing. This mechanism enables differentiated cells in a multicellular organism to 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; however, 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. These damages are largely repaired, but at the site of a DNA repair, epigenetic changes can remain. 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. However, this can be misleading. Chromatin remodeling is not always inherited, and not all epigenetic inheritance involves chromatin remodeling. 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 Cp. G sites, to convert cytosine to 5- methylcytosine. 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 . 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 K1. 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 . 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. In other words, changes to the histone tails have a direct effect on the DNA itself. Another model of epigenetic function is the . 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 . 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 1. This domain has been demonstrated to bind to the histone tail and causes the methylation of the histone. 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\'. 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, DNMT3. A, and DNMT3. B, the loss of any of which is lethal in mice. This recently identified enzyme has a catalytically active site called the Jumonji domain (Jmj. C). The demethylation occurs when Jmj. C utilizes multiple cofactors to hydroxylate the methyl group, thereby removing it. Jmj. C is capable of demethylating mono- , di- , and tri- methylated substrates. Epigenetic control is often associated with alternative covalent modifications of histones. Small interfering RNAs can modulate transcriptional gene expression via epigenetic modulation of targeted promoters. For example, Hnf. Myo. D 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. 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.
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