Molecular Regulation of Histone H3 Trimethylation by COMPASS and the Regulation of Gene Expression

Abstract

The Set1-containing complex COMPASS, which is the yeast homolog of the human MLL complex, is required for mono-, di-, and trimethylation of lysine 4 of histone H3. We have performed a comparative global proteomic screen to better define the role of COMPASS in histone trimethylation. We report that both Cps60 and Cps40 components of COMPASS are required for proper histone H3 trimethylation, but not for proper regulation of telomere-associated gene silencing. Purified COMPASS lacking Cps60 can mono- and dimethylate but is not capable of trimethylating H3(K4). Chromatin immunoprecipitation (ChIP) studies indicate that the loss subunits of COMPASS required for histone trimethylation do not affect the localization of Set1 to chromatin for the genes tested. Collectively, our results suggest a molecular requirement for several components of COMPASS for proper histone H3 trimethylation and regulation of telomere-associated gene expression, indicating multiple roles for different forms of histone methylation by COMPASS.

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

“…Histone lysine methylation can occur in mono-, di-, or trimethylated forms [8][9][10]. The same enzyme can either implement each state in a processive manner, or in some cases, different enzymes can be required for different methylation states on the same residue [8,10] (Figure 1).…”

“…The same enzyme can either implement each state in a processive manner, or in some cases, different enzymes can be required for different methylation states on the same residue [8,10] (Figure 1). The biological ramifications of histone methylations in transcriptional regulation are quite diverse.…”

“…The first H3K4 methylase complex, COMPASS, was identified in the yeast S. cerevisiae and consists of Set1/KMT2 and seven other polypeptides (named Cps60-Cps15) [24]. Set1/KMT2 alone is not enzymatically active, but functions within COMPASS and is capable of mono-, di-, and trimethylating H3K4 [6,8,10,[24][25][26][27]. Following the identification of Set1/COMPASS as an H3K4 methylase, it was demonstrated that its mammalian homologues, the MLL proteins, MLL1-4 and hSet1A and B, are found in COMPASS-like complexes capable of methylating the fourth lysine of histone H3 [6,28,29] (Figure 2).…”

RNF20–RNF40: A ubiquitin‐driven link between gene expression and the DNA damage response

“…The first breakthrough came with the identification of the budding yeast protein Bre1 [38,39], which, together with the ubiquitin-conjugating enzyme Rad6, serves as the E3 ligase in the monoubiquitylation of the yeast histone H2B on lysine 123 (K123) within transcribed chromatin [38][39][40][41]. Notably, H2B monoubiquitylation was subsequently found to be required for di-and trimethylation of lysine 4 and lysine 79 of histone H3 at transcribed chromatin [42][43][44][45][46][47][48]. This pathway is conserved from yeast to mammals, and is dependent on a host of additional proteins that converge at the elongating RNA Pol II [41,[49][50][51][52][53][54].…”

Assembling a COMPASS

“…Finally, Roguev et al identified Shg1 as a subunit of COMPASS, however no mammalian homologs of this protein has been identified thus far 8 and the loss of Shg1 has no effect on COMPASS stability or the pattern of H3K4 methylation. Along with studies on mammalian COMPASS-like complexes, [22][23][24][25][26][27] these findings illustrated the complexity of these multi-subunit protein machineries and established the foundation to perform detailed molecular analysis on the role of each subunit in the assembly and function of COMPASS.…”