Histone Modification Enzymes: Exploring the Writers and Erasers

The writers and erasers of histone methylation and acetylation

Histones undergo a number of post-translational modifications, including methylation and acetylation, which regulate transcription and gene expression. The enzymes responsible for adding or removing these epigenetic marks are often referred to as “writers” and “erasers”, respectively. In histone methylation, histone methyltransferasesadd the methyl mark and histone demethylasesremove the methylation; while in acetylating histones, histone acetyltransferasescatalyze the addition of acetyl groups and histone deacetylasesremove the acetylation mark.

The Writers

HMTs catalyze the transfer of one to three methyl groups to the Ɛ-amino or ω-guanidino groups of lysine or arginine residues, respectively. They include histone lysine methyltransferases (HKMTs) and histone protein arginine methyltransferases (PRMTs). Lysines can be mono, di, or tri-methylated, whereas arginines can be mono or di-methylated (symmetrically or asymmetrically). S-adenosylmethionine (SAM) is used as the methyl donor.

The lysine methyltransferases are highly specific enzymes and a particular aromatic residue in their catalytic site determines whether the lysine will be further methylated to di- or tri-methylated, after the mono-methylation. For example, enzymes with a phenylalanine residue in the catalytic site can accommodate the fully methylated form, whereas a tyrosine residue can only accommodate the mono-methylated form. Mutation of these amino acids can change the specificity of the enzyme. Some well-known lysine methyltransferases include EZH2, DOT1, and SUV39H1 and SUV39H2.

The protein arginine methyltransferases are divided into two types: type I and type II. Both catalyze mono-methylation, however type I catalyzes asymmetric di-methylation while type II catalyzes symmetric di-methylation. The best known PRMTs, include PRMT1, PRMT4, PRMT5, and PRMT6.

Structure of Class I and II HDACs. Source: Seto, E. and Yoshida, M. (2014).

The HATs catalyze the addition of an acetyl group to the Ɛ-amino side chain of lysine residues in histones, using acetyl-CoA as cofactor. They are generally associated with multiprotein complexes containing transcriptional coactivators. The HATs are divided into 2 major types: Type A and Type B. The Type A HATs are predominantly nuclear and acetylate nucleosome-associated histones. These can be subdivided into 3 families: GNAT, MYST, and CBP 300. Type B HATs are mostly localized to the cytoplasm, and acetylate free newly synthesized histones in the cytoplasm, prior to incorporation into chromatin.

The Erasers

There are two major groups of histone lysine demethylases (KDMs), the lysine specific demethylases (LSDs or KDM1) and the JmjC-domain containing proteins (KDM2-8). The KDM1 enzymes are dependent on flavin for activity, while the JmjC KDMs require alpha-ketoglutarate and Fe (II). Similar to lysine methyltransferases, lysine demethylases are also highly specific, with some catalyzing demethylation on mono or di-methylated residues, whereas others catalyze removal on tri-methylated lysines. Much less is known about demethylation at the arginine residues. It has been proposed that a subset of JmjC KDMs, including JMJD6, are capable of catalyzing demethylation at arginine residues. Important demethylases include LSD1, the JARID family, JMJDs, and UTX.

HDACs catalyze the removal of the acetyl group from histones and restore the positive charge of the lysine residues, stabilizing electrostatic interactions and leading to repression of transcription. They are grouped into four classes. Class I HDACs include HDAC1, HDAC2, HDAC3 and HDAC8. Class II comprises HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10. Class III are the Sirtuins or SIRTs, which include SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6 and SIRT7; and Class IV only contains HDAC11. Unlike the other HDACs, the SIRTs require NAD+ as cofactor for their activity.