The n-SET Domain of Set1 Regulates H2B Ubiquitylation-Dependent H3K4 Methylation

• Published in: Molecular cell Vol. 49; no. 6; pp. 1121 - 1133
• Main Authors: Kim, Jaehoon, Kim, Jung-Ae, McGinty, Robert K., Nguyen, Uyen T.T., Muir, Tom W., Allis, C. David, Roeder, Robert G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.03.2013
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Animals; Catalytic Domain; Chromatin - chemistry; DNA-Binding Proteins - chemistry; HeLa Cells; Histone-Lysine N-Methyltransferase - chemistry; Histones - chemistry; Humans; Methylation; Molecular Sequence Data; Multiprotein Complexes - chemistry; Protein Binding; Protein Interaction Domains and Motifs; Protein Subunits - chemistry; Saccharomyces cerevisiae - enzymology; Saccharomyces cerevisiae Proteins - chemistry; Sf9 Cells; Spodoptera; Ubiquitination; Xenopus Proteins - chemistry
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2013.01.034

Past studies have documented a crosstalk between H2B ubiquitylation (H2Bub) and H3K4 methylation, but little (if any) direct evidence exists explaining the mechanism underlying H2Bub-dependent H3K4 methylation on chromatin templates. Here, we took advantage of an in vitro histone methyltransferase assay employing a reconstituted yeast Set1 complex (ySet1C) and a recombinant chromatin template containing fully ubiquitylated H2B to gain valuable insights. Combined with genetic analyses, we demonstrate that the n-SET domain within Set1, but not Swd2, is essential for H2Bub-dependent H3K4 methylation. Spp1, a homolog of human CFP1, is conditionally involved in this crosstalk. Our findings extend to the human Set1 complex, underscoring the conserved nature of this disease-relevant crosstalk pathway. As not all members of the H3K4 methyltransferase family contain n-SET domains, our studies draw attention to the n-SET domain as a predictor of an H2B ubiquitylation-sensing mechanism that leads to downstream H3K4 methylation. [Display omitted] ► H2B ubiquitylation directly stimulates H3K4 methylation by the yeast Set1 complex ► Swd2 is not directly required for the H3K4 methylation activity of the yeast Set1 complex ► The Set1 n-SET domain plays a critical role in H2Bub-dependent H3K4 methylation ► Spp1 is conditionally involved in n-SET- and H2Bub-dependent H3K4 methylation