The Hbo1-Brd1/Brpf2 complex is responsible for global acetylation of H3K14 and required for fetal liver erythropoiesis

Blood - Tập 118 - Trang 2443-2453 - 2011
Yuta Mishima1,2, Satoru Miyagi1,2, Atsunori Saraya1,2, Masamitsu Negishi1,2, Mitsuhiro Endoh2,3, Takaho A. Endo4, Tetsuro Toyoda4, Jun Shinga3, Takuo Katsumoto5, Tetsuhiro Chiba1,2, Naoto Yamaguchi6, Issay Kitabayashi5, Haruhiko Koseki2,3, Atsushi Iwama1,2
1Department of Cellular and Molecular Medicine, Graduate School of Medicine, and
2JST, CREST, Tokyo, Japan
3RIKEN Research Center for Allergy and Immunology, Yokohama, Japan
4RIKEN Genomic Sciences Center, Yokohama, Japan; and
5Molecular Oncology Division, National Cancer Center Research Institute, Tokyo, Japan
6Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan

Tóm tắt

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.

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