(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 (see figure). 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 the 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) (see bottom figure). 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 (see top figure). 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 orchestrate 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 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-specific 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 a mirna database. each mirna expressed in a cell may target about 100 to 200 messenger rnas(mrnas) 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. 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 further information: fungal 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. prion-based epigenetics has also been observed in saccharomyces cerevisiae. structural inheritance further information: structural inheritance 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. nucleosome positioning eukaryotic genomes have numerous nucleosomes. nucleosome position is not random, and determine the accessibility of dna to regulatory proteins. promoters active in different tissues have been shown to have different nucleosome positioning features. this determines differences in gene expression and cell differentiation. it has been shown that at least some nucleosomes are retained in sperm cells (where most but not all histones are replaced by protamines). thus nucleosome positioning is to some degree inheritable. recent studies have uncovered connections between nucleosome positioning and other epigenetic factors, such as dna methylation and hydroxymethylation. histone variants different histone variants are incorporated into specific regions of the genome non-randomly. their differential biochemical characteristics can affect genome functions via their roles in gene regulation, and maintenance of chromosome structures. genomic architecture the three-dimensional configuration of the genome (the 3d genome) is complex, dynamic and crucial for regulating genomic function and nuclear processes such as dna replication, transcription and dna-damage repair. functions and consequences in the brain