title: Context dependency of Set1/COMPASS-mediated histone H3 Lys4 trimethylation.
abstract: The stimulation of trimethylation of histone H3 Lys4 (H3K4) by H2B monoubiquitination (H2Bub) has been widely studied, with multiple mechanisms having been proposed for this form of histone cross-talk. Cps35/Swd2 within COMPASS (complex of proteins associated with Set1) is considered to bridge these different processes. However, a truncated form of Set1 (762-Set1) is reported to function in H3K4 trimethylation (H3K4me3) without interacting with Cps35/Swd2, and such cross-talk is attributed to the n-SET domain of Set1 and its interaction with the Cps40/Spp1 subunit of COMPASS. Here, we used biochemical, structural, in vivo, and chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq) approaches to demonstrate that Cps40/Spp1 and the n-SET domain of Set1 are required for the stability of Set1 and not the cross-talk. Furthermore, the apparent wild-type levels of H3K4me3 in the 762-Set1 strain are due to the rogue methylase activity of this mutant, resulting in the mislocalization of H3K4me3 from the promoter-proximal regions to the gene bodies and intergenic regions. We also performed detailed screens and identified yeast strains lacking H2Bub but containing intact H2Bub enzymes that have normal levels of H3K4me3, suggesting that monoubiquitination may not directly stimulate COMPASS but rather works in the context of the PAF and Rad6/Bre1 complexes. Our study demonstrates that the monoubiquitination machinery and Cps35/Swd2 function to focus COMPASS's H3K4me3 activity at promoter-proximal regions in a context-dependent manner.
authors.affiliation: Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA;
authors.forename: Janet L
authors.initials: JL
authors.lastname: Thornton
authors.forename: Gerwin H
authors.initials: GH
authors.lastname: Westfield
authors.forename: Yoh-Hei
authors.initials: YH
authors.lastname: Takahashi
authors.forename: Malcolm
authors.initials: M
authors.lastname: Cook
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Woodfin
authors.forename: Jung-Shin
authors.initials: JS
authors.lastname: Lee
authors.forename: Marc A
authors.initials: MA
authors.lastname: Morgan
authors.forename: Jessica
authors.initials: J
authors.lastname: Jackson
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Smith
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Couture
authors.forename: Georgios
authors.initials: G
authors.lastname: Skiniotis
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
mesh_terms: D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008745:Methylation; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D055550:Protein Stability; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D006657:Histones; D008565:Membrane Proteins; D029701:Saccharomyces cerevisiae Proteins; D011495:Histone-Lysine N-Methyltransferase; C411250:SET1 protein, S cerevisiae; C401298:sphingosine-1-phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases; D008239:Lysine
keywords: chromatin; gene expression; histone; transcription