The COMPASS Family of Histone H3K4 Methylases: Mechanisms of Regulation in Development and Disease Pathogenesis

Abstract

The Saccharomyces cerevisiae Set1/COMPASS was the first histone H3 lysine 4 (H3K4) methylase identified over ten years ago. Since then, it has been demonstrated that Set1/COMPASS and its enzymatic product, H3K4 methylation, is highly conserved across the evolutionary tree. Although there is only one COMPASS in yeast, human cells bear at least six COMPASS family members each capable of methylating H3K4 with non-redundant functions. In yeast, the monoubiquitination of histone H2B by Rad6/Bre1 is required for proper H3K4 and H3K79 trimethylations. This histone crosstalk and its machinery are also highly conserved from yeast to human. In this review, the process of histone H2B monoubiquitination-dependent and independent histone H3K4 methylation as a mark of active transcription, enhancer signatures, and developmentally poised genes will be discussed. The misregulation of histone H2B monoubiquitination and H3K4 methylation results in the pathogenesis of human diseases including cancer. Recent findings in this regard will also be examined.

The Set1/COMPASS Histone H3 Methyltransferase Helps Regulate Mitosis With the CDK1 and NIMA Mitotic Kinases in Aspergillus nidulans

“…For a wild-type strain, H3K4 mono-, di-, and trimethylation was readily detected in total cell extracts but no methylation was detected in the DAn-set1 or DAn-swd1 strains ( Figure S2). This result is consistent with the Set1 complex mediating mono-, di-, and trimethylation at histone H3K4 in A. nidulans, similar to other organisms (Krogan et al 2002;Noma and Grewal 2002;Dehe and Geli 2006;Shilatifard 2012;Palmer et al 2013).…”

“…For a wild-type strain, H3K4 mono-, di-, and trimethylation was readily detected in total cell extracts but no methylation was detected in the DAn-set1 or DAn-swd1 strains ( Figure S2). This result is consistent with the Set1 complex mediating mono-, di-, and trimethylation at histone H3K4 in A. nidulans, similar to other organisms (Krogan et al 2002;Noma and Grewal 2002;Dehe and Geli 2006;Shilatifard 2012;Palmer et al 2013).In addition to the methylation of H3 at K4, the Set1 complex has also been shown to methylate the kinetochore protein Dam1 in S. cerevisiae (Zhang et al 2005). To determine whether the histone H3K4 target site of the Set1 complex was involved in the synthetic growth defects with partial NIMA or CDK1 function (Figure 1), we generated strains carrying a mutant version of histone H3, where the lysine K4 was changed to arginine (H3K4R).…”

“…Methylation of Dam1 by the Set1 complex inhibits Ipl1-mediated phosphorylation and therefore helps modulate the phosphorylation state of Dam1 and chromosome segregation fidelity in yeast (Zhang et al 2005). Finally, the rearrangement of the human ortholog of Set1 gene (mixed lineage leukemia, MLL) is widely seen in several aggressive human leukemias, further underlining the importance of fully understanding the network of proteins that function along with Set1 complexes (Shilatifard 2012).…”

Coactivators and general transcription factors have two distinct dynamic populations dependent on transcription

“…We used siRNA to knock down ASHL2, a core subunit of the SET1/MLL/COMPASS‐like methyltransferase complexes (Shilatifard, 2012), causing efficient reduction in H3K4me3 levels (Fig 7C; see also Steward et al , 2006). We performed FCS for transiently expressed eGFP‐SGF29 in cells previously transfected with siRNA against ASH2L, and observed significantly reduced chromatin interactions (Fig 7D).…”

Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer

“…Dynamic methylation and demethylation of H3K4 is primarily facilitated by the trithorax (TrxG) members of histone methyltransferases (HMT) termed SETD1A/B and MLL1-4 (27), and the histone demethylases LSD1/2 (28) and JARID1A-D (29)(30)(31)(32). hSETD1A mainly catalyzes H3K4me3 and is thus an important coactivator of gene transcription (27).…”