title: The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3K14 and required for fetal liver erythropoiesis.
abstract: The histone acetyltransferases (HATs) of the MYST family include TIP60, HBO1, MOZ/MORF, and MOF and function in multisubunit protein complexes. Bromodomain-containing protein 1 (BRD1), also known as BRPF2, has been considered a subunit of the MOZ/MORF H3 HAT complex based on analogy with BRPF1 and BRPF3. However, its physiologic function remains obscure. Here we show that BRD1 forms a novel HAT complex with HBO1 and regulates erythropoiesis. Brd1-deficient embryos showed severe anemia because of impaired fetal liver erythropoiesis. Biochemical analyses revealed that BRD1 bridges HBO1 and its activator protein, ING4. Genome-wide mapping in erythroblasts demonstrated that BRD1 and HBO1 largely colocalize in the genome and target key developmental regulator genes. Of note, levels of global acetylation of histone H3 at lysine 14 (H3K14) were profoundly decreased in Brd1-deficient erythroblasts and depletion of Hbo1 similarly affected H3K14 acetylation. Impaired erythropoiesis in the absence of Brd1 accompanied reduced expression of key erythroid regulator genes, including Gata1, and was partially restored by forced expression of Gata1. Our findings suggest that the Hbo1-Brd1 complex is the major H3K14 HAT required for transcriptional activation of erythroid developmental regulator genes.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Graduate School of Pharmaceutical, Sciences, Chiba University, Chiba, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Mishima
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyagi
authors.forename: Atsunori
authors.initials: A
authors.lastname: Saraya
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Negishi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Endoh
authors.forename: Takaho A
authors.initials: TA
authors.lastname: Endo
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Toyoda
authors.forename: Jun
authors.initials: J
authors.lastname: Shinga
authors.forename: Takuo
authors.initials: T
authors.lastname: Katsumoto
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Chiba
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Issay
authors.initials: I
authors.lastname: Kitabayashi
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
mesh_terms: D000107:Acetylation; D000740:Anemia / Q000196:embryology / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D004249:DNA Damage; D004261:DNA Replication; D004920:Erythropoiesis; D005313:Fetal Death / Q000097:blood / Q000209:etiology / Q000235:genetics; D050982:GATA1 Transcription Factor / Q000378:metabolism; D005804:Genes, Lethal; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D020014:K562 Cells; D008099:Liver / Q000196:embryology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000494:pharmacology; D015534:Trans-Activators / Q000172:deficiency / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000502:physiology; D000092468:Bromodomain Containing Proteins
chemical_list: D002352:Carrier Proteins; D050982:GATA1 Transcription Factor; D051548:Histone Acetyltransferases; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C562256:BRD1 protein, mouse; D000092468:Bromodomain Containing Proteins; C494689:Gata1 protein, mouse; C540680:ING4 protein, mouse; C525638:Kat7 protein, mouse