Epigenetics

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Epigenetics

Epigenetics is the complex term of all reversible modifications of DNA and chromatin that do not change the underlying DNA nucleotide sequence, but regulate gene expression. Conrad Waddington (1905–1975), who is given credit for coining the term, defined epigenetics as “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being”. It is well established that anomalous epigenetic signaling has a crucial role in tumorigenesis, but it can also be an important determinant of cellular senescence and organism aging. The best known epigenetic modifications are DNA methylation and post-transcriptional histone modifications, including methylation, acetylation, ubiquitylation and phosphorylation.

DNA methylation is perhaps the best characterized chemical modification of chromatin. In mammals, nearly all DNA methylation occurs on cytosine residues of CpG dinucleotides. Regions of the genome that have a high density of CpGs are referred to as CpG islands, and DNA methylation of these islands correlates with transcriptional repression. Genomic patterns of cytosine methylation in mammals, whether donated by de novo or maintenance DNA methyltransferases (DNMTs), play a critical role in gene regulation and chromatin organization during embryogenesis and gametogenesis. The formation of heterochromatin in many organisms is mediated in part by DNA methylation and its binding proteins in combination with RNA and histone modifications characteristic of silent chromatin. DNA methylation plays a role in many cellular processes including silencing of repetitive and centromeric sequences from fungi to mammals; X chromosome inactivation in female mammals; and mammalian imprinting, all of which can be stably maintained. DNA methylation provides a stable, heritable, and critical component of epigenetic regulation. Also RNA, particularly noncoding RNAs, have a hand in controlling multiple epigenetic phenomena. Clear examples of RNA involvement range from dosage compensation mechanisms in Drosophila and mammals mediated by the rox and XIST RNAs, respectively, to the silencing of both genes and repetitive DNA sequences by posttranscriptional (PTGS) and transcriptional (TGS) RNA interference (RNAi)-related pathways, respectively, in almost all eukaryotes. The list of covalent modifications to histone proteins continues to grow. Noncovalent mechanisms such as chromatin remodeling and the incorporation of specialized histone variants provide the cell with additional tools for introducing variation into the chromatin template. ATP-dependent chromatin remodeling complexes are thought to modify chromatin accessibility by altering histoneDNA interactions, perhaps by sliding or ejecting nucleosomes. In addition, histone variants such as H3.3 and H2A.Z, often carrying their own modification patterns, are exchanged within chromosomal domains by dedicated chaperone and exchange machinery. There are two classical evolutionarily conserved families of proteins that regulate homeotic genes antagonistically during development: the Polycomb Group (PcG) and the Trithorax Group (TrxG). Further molecular characterization of PcG proteins reveals that they contribute to two distinct protein complexes that are responsible for “writing” (PRC2, Polycomb Repressive Complex 2) and “reading” (PRC1) methylation of H3K27 and facilitating chromatin condensation. Meanwhile, TrxG proteins mediate methylation of H3K4 and promote transcriptionally active chromatin.

The great fidelity with which DNA methylation patterns in mammals are inherited after each cell division is ensured by the DNA methyltransferases (DNMTs). However, the aging cell undergoes a DNA methylation drift. Early studies showed that global DNA methylation decreases during aging in many tissue types, and it was subsequently observed that mammalian fibroblasts cultured to senescence increasingly lost DNA methylation. The natural response of the cell to loss of DNA methylation in repeated DNA sequences is the overexpression of the de novo DNA methylase DNMT3b. A logical outcome of DNMT3b overexpression is that regions such as promoter CpG islands, which are commonly unmethylated in normal cells, become aberrantly hypermethylated, as previously reported for human mutL homolog 1 (MLH1) and p14ARF genes. Several specific regions of the genomic DNA become hypermethylated during aging. For instance, there is an increase of methylcytosine within the ribosomal DNA clusters in livers of senescent rats. Histone modifications also have a defined profile during aging and cell transformation. For example, the trimethylation of H4-K20, which is enriched in differentiated cells, increases with age, is commonly reduced in cancer cells. The increase of trimethylated H4-K20 in aged-like cells has been associated with defects in the nuclear lamina. The loss of trimethylated H4- K20 in cancer can be caused by the loss of expression of the H4-K20-specific methyltranferase Suv4-20h, loss of the tumor suppressor retinoblastoma, or deregulation of other histone-modifying enzymes.