BRPF1 is essential for development of fetal hematopoietic stem cells
Linya You, Lin Li, Jinfeng Zou, Kezhi Yan, Jad Belle, Anastasia Nijnik, Edwin Wang, Xiang-Jiao Yang
Linya You, Lin Li, Jinfeng Zou, Kezhi Yan, Jad Belle, Anastasia Nijnik, Edwin Wang, Xiang-Jiao Yang
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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 7

Brpf1 deletion alters LSK cell programs.

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Brpf1 deletion alters LSK cell programs. (A and B) After staining with ...
(A and B) After staining with antibodies against lineage-specific markers (PerCPCy5.5-conjugated CD3ε, B220, Gr1, and Ter119) together with antibodies specific for HSC markers (Sca1-APC and cKit-Pacific blue), P6 bone marrow cells were fixed, permeabilized, and restained with Ki67-FITC. n = 7 for control and n = 4 for Brpf1fl/fl Vav1-iCre (vKO) pups. (C) Bone marrow cells were stained with the antibodies as in A and B, except that Ki67-FITC was replaced with annexin V-PECy7. n = 6 for control and n = 4 for vKO. (D) Percentage of ROS-positive cells in LSK, CD150+LSK, CD150–LSK, and MP populations in the control and mutant bone marrows at P9. n = 3 for each group. (E) Percentage of senescent cells in LSK, CD150+LSK, CD150–LSK, and MP fractions in the control and mutant bone marrows at P9. n = 6 for control pups and n = 3 for vKO pups. *P < 0.05, **P < 0.01, ***P < 0.001. For statistical analysis, unpaired 2-tailed Student’s t tests were performed; average values are presented as the mean + SEM in A–C and as the mean ± SEM in D and E.