BRPF1 is essential for development of fetal hematopoietic stem cells

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DOIResolve DOI: http://doi.org/10.1172/JCI80711
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TypeArticle
Journal titleJournal of Clinical Investigation
ISSN0021-9738
1558-8238
AbstractHematopoietic 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.
Publication date
PublisherAmerican Society for Clinical Investigation
LanguageEnglish
AffiliationHuman Health Therapeutics; National Research Council Canada
Peer reviewedYes
NPARC number23000645
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Record identifier9cacff12-f201-4009-9908-4fce5f32af9a
Record created2016-08-17
Record modified2016-08-17
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