BRPF1 is essential for development of fetal hematopoietic stem cells
Linya You, … , Edwin Wang, Xiang-Jiao Yang
Linya You, … , Edwin Wang, Xiang-Jiao Yang
Published August 8, 2016
Citation Information: J Clin Invest. 2016;126(9):3247-3262. https://doi.org/10.1172/JCI80711.
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Research Article Stem cells

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 You, Lin Li, Jinfeng Zou, Kezhi Yan, Jad Belle, Anastasia Nijnik, Edwin Wang, Xiang-Jiao Yang

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Figure 1

Brpf1-deficient mice display postnatal lethality and severe hematopoietic hypoplasia.

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Brpf1-deficient mice display postnatal lethality and severe hematopoiet...
(A) Kaplan-Meier survival curve. Twenty-four pairs of control and Brpf1fl/fl Vav1-iCre (vKO) mice were monitored for survival. Mutant mice were alive for a maximum of 21 days with median mortality at P18. (B–E) Unlike the control, mutant mice exhibited pale extremities (B) and pale liver (C), along with small spleen (D) and thymus (E) at week 3 after birth. Three pairs were examined and images for 1 representative pair of P19 control and mutant mice are shown. S, spleen. (F and H) H&E staining of P19 spleen (F) and thymus (H) paraffin sections. (G and I) Magnified images taken from F and H, respectively. Note abnormal histological organizations in mutant sections. Scale bars: B–E, 5 mm; F and H, 1 mm; G and I, 100 μm.