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

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 2

Brpf1 deletion leads to acute bone marrow failure.

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Brpf1 deletion leads to acute bone marrow failure. (A and B) H&E st...
(A and B) H&E staining of long-bone sections from representative control and Brpf1fl/fl Vav1-iCre (vKO) pups at P16 and P12. (C and D) Giemsa staining of long-bone sections (C) and bone marrow smears (D) from P12 control and mutant pups, confirming low cellularity in the mutant. (E and F) H&E staining of long-bone sections from control and mutant pups at P2 and P5. At each time point, 3 pairs from 3 different litters were examined and images from 1 representative pair are shown here. Scale bars: 200 μm in A, B, E, and F; 100 μm in C and D.