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 3

Depleted HSC and hematopoietic progenitor populations in the mutant bone marrow.

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Depleted HSC and hematopoietic progenitor populations in the mutant bone...
(A and B) Representative cytometric analysis of LSK cells, myeloid progenitors, and common lymphoid progenitors in control and Brpf1fl/fl Vav1-iCre (vKO) bone marrow. P6 bone marrow cells were stained with fluorophore-conjugated monoclonal antibodies for cytometric detection of the following populations of stem cell or progenitor populations: MP (myeloid progenitor), LSK, MEP (megakaryocyte/erythroid progenitor), CMP (common myeloid progenitor), GMP (granulocyte/macrophage progenitor), common lymphoid progenitor (CLP), and IL-7Rα– LSK (enriched for HSCs). (C and D) Percentage values of different populations detected in A and B. n = 5 for each genotype. (E) Representative cytometric analysis of bone marrow HSCs, MPPs (multipotent progenitors), and HPCs (hematopoietic progenitor cells) gated according to expression of the SLAM (signaling lymphocytic activation molecule) cell surface markers CD48 and CD150. (F and G) Within LSK cells, HPC ratios were not altered in the mutant (F). Because the percentage of LSK cells was much lower in the mutant bone marrow (B), all 4 populations decreased dramatically in the mutant (G). n = 7 for wild-type and n = 3 for vKO pups. No significant difference was observed between wild-type and heterozygous LSK cell numbers: 0.18% ± 0.01% (wild-type, n = 4) vs. 0.22% ± 0.02% (heterozygous, n = 4). *P < 0.05, ***P < 0.001. For statistical analysis, unpaired 2-tailed Student’s t tests were performed and average values are shown as the mean + SEM in C, D, F, and G.