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 5

Brpf1 deletion reduces HSC and B cell populations in the fetal liver.

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Brpf1 deletion reduces HSC and B cell populations in the fetal liver. (...
(A–D) Total cellularity (A), LSK cells (B), and 4 stem/progenitor populations (HPC1, HPC2, HSC, and MPP; C and D) in the fetal liver of control vs. Brpf1fl/fl Vav1-iCre (vKO) mice at E12.5. (E) Percentage values of LSK cells, myeloid progenitor, and different fractions (CMP, GMP, and MEP) in the E14.5 fetal liver. Numbers of CMPs and GMPs, but not LSK cells, MPs, or MEPs, decreased in the mutant. (F) Percentage values of the 4 fractions gated according to expression of CD48 and CD150. Despite the similar cell number of LSKs (E), the HSC fraction declined, whereas the HPC1 fraction slightly increased in the mutant. (G–I) B lymphoid (G), myeloid (H), and erythroid cells (I) were compared between control and vKO fetal livers at E14.5. Percentage values of Gr1+ cells, CD19+ B lineage cells, Mac1+Gr1lo monocytes, Mac1+Gr1hi granulocytes, and 4 erythroid fractions are shown. B lineage cells disappeared but myelopoiesis showed a mild increase in the mutant. (J–L) Proliferation and apoptosis of LSK cells in the E14.5 fetal liver. n = 8 for control and n = 4 for vKO in A–D; n = 7 for control and n = 3 for vKO in E–I; n = 8 for control and n = 5 for vKO in J–L; *P < 0.05, **P < 0.01, ***P < 0.001. For statistical analysis, unpaired 2-tailed Student’s t tests were performed and average values are presented here as the mean + SEM.