title: Polycomb inhibits histone acetylation by CBP by binding directly to its catalytic domain.
abstract: Drosophila Polycomb (PC), a subunit of Polycomb repressive complex 1 (PRC1), is well known for its role in maintaining repression of the homeotic genes and many others and for its binding to trimethylated histone H3 on Lys 27 (H3K27me3) via its chromodomain. Here, we identify a novel activity of PC: inhibition of the histone acetylation activity of CREB-binding protein (CBP). We show that PC and its mammalian CBX orthologs interact directly with the histone acetyltransferase (HAT) domain of CBP, binding to the previously identified autoregulatory loop, whose autoacetylation greatly enhances HAT activity. We identify a conserved PC motif adjacent to the chromodomain required for CBP binding and show that PC binding inhibits acetylation of histone H3. CBP autoacetylation impairs PC binding in vitro, and PC is preferentially associated with unacetylated CBP in vivo. PC knockdown elevates the acetylated H3K27 (H3K27ac) level globally and at promoter regions of some genes that are bound by both PC and CBP. Conversely, PC overexpression decreases the H3K27ac level in vivo and also suppresses CBP-dependent Polycomb phenotypes caused by overexpression of Trithorax, an antagonist of Polycomb silencing. We find that PC is physically associated with the initiating form of RNA polymerase II (Pol II) and that many promoters co-occupied by PC and CBP are associated with paused Pol II, suggesting that PC may play a role in Pol II pausing. These results suggest that PC/PRC1 inhibition of CBP HAT activity plays a role in regulating transcription of both repressed and active PC-regulated genes.
authors.affiliation: Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106; fxt8@case.edu pjh3@case.edu.
authors.forename: Feng
authors.initials: F
authors.lastname: Tie
authors.affiliation: Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106;
authors.forename: Rakhee
authors.initials: R
authors.lastname: Banerjee
authors.affiliation: Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106;
authors.forename: Chen
authors.initials: C
authors.lastname: Fu
authors.affiliation: Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106;
authors.forename: Carl A
authors.initials: CA
authors.lastname: Stratton
authors.affiliation: Institute of Life Sciences and State Ministry of Education Key Laboratory of Developmental Genes and Human Diseases, Southeast University, Nanjing, China 210096.
authors.forename: Ming
authors.initials: M
authors.lastname: Fang
authors.affiliation: Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH 44106; fxt8@case.edu pjh3@case.edu.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Harte
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D020868:Gene Silencing; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008322:Mammals; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D010641:Phenotype; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D059007:Polytene Chromosomes / Q000378:metabolism; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism; D012469:Salivary Glands / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D006657:Histones; C066770:Pc protein, Drosophila; C524696:nej protein, Drosophila; D050880:p300-CBP Transcription Factors; D063150:Polycomb Repressive Complex 1; D012319:RNA Polymerase II; D008239:Lysine
keywords: CBP; Drosophila; Polycomb; acetylation; histone H3K27