title: Deubiquitylation of histone H2A activates transcriptional initiation via trans-histone cross-talk with H3K4 di- and trimethylation.
abstract: Transcriptional initiation is a key step in the control of mRNA synthesis and is intimately related to chromatin structure and histone modification. Here, we show that the ubiquitylation of H2A (ubH2A) correlates with silent chromatin and regulates transcriptional initiation. The levels of ubH2A vary during hepatocyte regeneration, and based on microarray expression data from regenerating liver, we identified USP21, a ubiquitin-specific protease that catalyzes the hydrolysis of ubH2A. When chromatin is assembled in vitro, ubH2A, but not H2A, specifically represses the di- and trimethylation of H3K4. USP21 relieves this ubH2A-specific repression. In addition, in vitro transcription analysis revealed that ubH2A represses transcriptional initiation, but not transcriptional elongation, by inhibiting H3K4 methylation. Notably, ubH2A-mediated repression was not observed when H3 Lys 4 was changed to arginine. Furthermore, overexpression of USP21 in the liver up-regulates a gene that is normally down-regulated during hepatocyte regeneration. Our studies revealed a novel mode of trans-histone cross-talk, in which H2A ubiquitylation controls the di- and trimethylation of H3K4, resulting in regulation of transcriptional initiation.
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
authors.forename: Takeya
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Takuya
authors.initials: T
authors.lastname: Kajitani
authors.forename: Shinji
authors.initials: S
authors.lastname: Togo
authors.forename: Norio
authors.initials: N
authors.lastname: Masuko
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohdan
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hishikawa
authors.forename: Takehiko
authors.initials: T
authors.lastname: Koji
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Matsuyama
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ikura
authors.forename: Masami
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
mesh_terms: D000818:Animals; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008954:Models, Biological; D008957:Models, Genetic; D024363:Transcription Initiation Site; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D002843:Chromatin; D006657:Histones; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; D006655:Histone Deacetylases; D008239:Lysine