Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation

Abstract

Chromosomal surfaces are ornamented with a variety of post-translational modifications of histones, which are required for the regulation of many of the DNA-templated processes. Such histone modifications include acetylation, sumoylation, phosphorylation, ubiquitination, and methylation. Histone modifications can either function by disrupting chromosomal contacts or by regulating non-histone protein interactions with chromatin. In this review, recent findings will be discussed regarding the regulation of the implementation and physiological significance for one such histone modification, histone H3 lysine 4 (H3K4) methylation by the yeast COMPASS and mammalian COMPASS-like complexes.

Figure 1. The known enzymatic machineries involved in the methylation of lysine residues of histones H3 and H4

The N-terminal amino acid sequences of histones H3 and H4 are shown along with the positions of specific methylation of lysines (in red) and arginines (in green) sites and the known enzymatic machinery responsible for the corresponding lysine modifications.

Figure 2. Subunit composition for COMPASS in yeast and its homologues in human

The founding member of the H3K4 methyltransferases, COMPASS, can momo-, di- and tirmethylate its substrate, histone H3. Human MLLs (MLL1-4) and hSet1 (hSet1A and B) are found in COMPASS like complexes capable of methylating H3K4 as well. In human, H3K4 methylase complex contains core subunits (shown in red) similar to that of COMPASS and complex specific subunits (shown in black). The methyltransferase function of MLLs in human are non-redundant as deletion of either MLLs result in embryonic lethality.

Figure 3. Translating histone crosstalk by COMPASS

Previous studies demonstrated that COMPASS interacts with the elongating form of Pol II via its interaction with the Paf1 complex [32, 43]. Therefore, (A) in the absence of H2B monoubiquitination, COMPASS can still interact with the transcribing Pol II via the Paf1 complex and monomethylate H3K4. (B) We now know that when histone H2B is monoubiquitinated, Cps35 can interact either directly or indirectly with chromatin through H2B monoubiquitination mark and associate with chromatin [49]. The association of Cps35 with chromatin facilitates the interaction between COMPASS and Cps35, resulting in the generation of a H3K4 trimethylation competent COMPASS [49].