Epigenetic Writers

Epigenetic writers catalyze the addition of chemical groups onto either histone tails or the DNA itself. These modifications are known as epigenetic marks, and are integral to gene expression and silencing.

One such group of epigenetic "writers" is histone methyltransferases, which are further subdivided into lysine methyltransferases and arginine methyltransferases according to their target residue. Protein lysine methyltransferases, also known as PKMTs, catalyze the transfer of a methyl group from the co-factor S-adenosyl methionine (SAM) onto a lysine side chain on the exposed histone tail. Histone lysine methylation can involve the transfer of one, two or three methyl groups onto a histone tail; the degree of methylation is of biological significance since proteins that interact with methylated histones are able to distinguish between mono-, di- and trimethylated lysines. Histone arginine residues may also undergo methylation, in a reaction catalyzed by protein arginine methyltransferases (PRMTs). PRMTs generate either monomethylated or dimethylated arginine residues, where the dimethylation can either occur symmetrically or asymmetrically. The symmetry of the methyl groups added to arginine residues determine the biological effect of the epigenetic modification: asymmetric dimethylation is linked to gene activation whilst symmetric dimethylation is associated with gene repression.

In addition to methyl marks, histone lysine residues may also undergo acetylation through the activity of histone acetyltransferases (HATs). The transfer of an acetyl group from the co-factor acetyl-CoA to lysine residues on histone tails neutralizes the positive charge of lysine; this weakens the affinity of the histone tail for the DNA and reduces chromatin condensation. Since a more relaxed, open chromatin architecture enables the recruitment of transcription factors and polymerases, histone acetylation results in the promotion of gene expression.

Enzymes that catalyze the phosphorylation of histone tails are also important epigenetic "writers". For example, phosphorylation of histone H3 (H3Y41) by JAK2 disrupts binding of the heterochromatin protein HP1α to chromatin, leading to increased DNA accessibility and the transcription of the oncogene lmo2. Other kinases including Haspin, Pim-1, PKC, and ATM/ATR kinases have also been implicated in the phosphorylation of histone proteins and subsequent modification of gene expression.

A further epigenetic mark that alters gene expression is ubiquitination. Lysine residues on histone proteins H2A and H2B can undergo monoubiquitination through the concerted actions of E2 ubiquitin conjugases and E3 ubiquitin ligases. Ubiquitin of histone H2A is associated with gene silencing through the involvement of repressive complexes including Polycomb repressive complex 1 (PRC1). In contrast, histone H2B ubiquitination has been suggested to act as a checkpoint for RNA polymerase activity, providing a stalling mechanism during early transcription elongation for the recruitment of Ctk1 to RNA polymerase II, and has been linked to both gene silencing and gene transcription. A further difference is that histone H2B is a pre-requisite for di- and tri-methylation of histone H3 Lys-9 (H3K9), whereas H2A ubiquitination inhibits histone lysine methylation.

DNA can also undergo methylation through different mechanisms. The addition of a methyl group to a nucleotide by DNA methyltransferases (DNMTs) occurs at the major groove of the DNA double helix, and prevents transcription by blocking the binding of transcription factors and polymerases. DNA methylation has a major involvement in embryonic development, genomic imprinting and the preservation of chromosome stability. There are two known types of DNA methylation - de novo and maintenance methylation. De novo methylation, predominantly carried out by DNA methyltransferases DNMT3A and DNMT3B, catalyzes the addition of methyl groups onto cytosine nucleotides. Since cell replication does not preserve such methylation, maintenance methylation copies these marks from the parent DNA onto the daughter DNA strands. The high affinity of DNMT1 for hemimethylated DNA in vitro suggests that this enzyme is primarily responsible for maintenance DNA methylation in vivo.

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