title: BRPF1 is essential for development of fetal hematopoietic stem cells.
abstract: Hematopoietic stem cells (HSCs) serve as a life-long reservoir for all blood cell types and are clinically useful for a variety of HSC transplantation-based therapies. Understanding the role of chromatin organization and regulation in HSC homeostasis may provide important insights into HSC development. Bromodomain- and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator that possesses 4 nucleosome-binding domains and activates 3 lysine acetyltransferases (KAT6A, KAT6B, and KAT7), suggesting that this protein has the potential to stimulate crosstalk between different chromatin modifications. Here, we investigated the function of BRPF1 in hematopoiesis by selectively deleting its gene in murine blood cells. Brpf1-deficient pups experienced early lethality due to acute bone marrow failure and aplastic anemia. The mutant bone marrow and fetal liver exhibited severe deficiency in HSCs and hematopoietic progenitors, along with elevated reactive oxygen species, senescence, and apoptosis. BRPF1 deficiency also reduced the expression of multipotency genes, including Slamf1, Mecom, Hoxa9, Hlf, Gfi1, Egr, and Gata3. Furthermore, BRPF1 was required for acetylation of histone H3 at lysine 23, a highly abundant but not well-characterized epigenetic mark. These results identify an essential role of the multivalent chromatin regulator BRPF1 in definitive hematopoiesis and illuminate a potentially new avenue for studying epigenetic networks that govern HSC ontogeny.
authors: Linya
authors: L
authors: You
authors: Lin
authors: L
authors: Li
authors: Jinfeng
authors: J
authors: Zou
authors: Kezhi
authors: K
authors: Yan
authors: Jad
authors: J
authors: Belle
authors: Anastasia
authors: A
authors: Nijnik
authors: Edwin
authors: E
authors: Wang
authors: Xiang-Jiao
authors: XJ
authors: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D016922:Cellular Senescence; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins; D044127:Epigenesis, Genetic; D005260:Female; D017353:Gene Deletion; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006706:Homeostasis; D008099:Liver / Q000196:embryology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072417:Protein Domains; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006657:Histones; D017382:Reactive Oxygen Species; C000597967:BRPF1 protein, mouse; D000092468:Bromodomain Containing Proteins