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HDAC3 is essential for DNA replication in hematopoietic progenitor cells
Alyssa R. Summers, … , David Cortez, Scott W. Hiebert
Alyssa R. Summers, … , David Cortez, Scott W. Hiebert
Published June 10, 2013
Citation Information: J Clin Invest. 2013;123(7):3112-3123. https://doi.org/10.1172/JCI60806.
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Research Article Hematology

HDAC3 is essential for DNA replication in hematopoietic progenitor cells

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Abstract

Histone deacetylase 3 (HDAC3) contributes to the regulation of gene expression, chromatin structure, and genomic stability. Because HDAC3 associates with oncoproteins that drive leukemia and lymphoma, we engineered a conditional deletion allele in mice to explore the physiological roles of Hdac3 in hematopoiesis. We used the Vav-Cre transgenic allele to trigger recombination, which yielded a dramatic loss of lymphoid cells, hypocellular bone marrow, and mild anemia. Phenotypic and functional analysis suggested that Hdac3 was required for the formation of the earliest lymphoid progenitor cells in the marrow, but that the marrow contained 3–5 times more multipotent progenitor cells. Hdac3–/– stem cells were severely compromised in competitive bone marrow transplantation. In vitro, Hdac3–/– stem and progenitor cells failed to proliferate, and most cells remained undifferentiated. Moreover, one-third of the Hdac3–/– stem and progenitor cells were in S phase 2 hours after BrdU labeling in vivo, suggesting that these cells were impaired in transit through the S phase. DNA fiber-labeling experiments indicated that Hdac3 was required for efficient DNA replication in hematopoietic stem and progenitor cells. Thus, Hdac3 is required for the passage of hematopoietic stem/progenitor cells through the S phase, for stem cell functions, and for lymphopoiesis.

Authors

Alyssa R. Summers, Melissa A. Fischer, Kristy R. Stengel, Yue Zhao, Jonathan F. Kaiser, Christina E. Wells, Aubrey Hunt, Srividya Bhaskara, Jessica W. Luzwick, Shilpa Sampathi, Xi Chen, Mary Ann Thompson, David Cortez, Scott W. Hiebert

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Figure 5

Hdac3 is required for stem cell functions.

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Hdac3 is required for stem cell functions.
 
(A) Competitive repopulati...
(A) Competitive repopulation assay in which 90% control (empty bars) or Hdac3–/– (filled bars) CD45.2+ bone marrow cells were coinjected with 10% WT CD45.1+ cells, and peripheral blood was analyzed by FACS. Data shown are the mean ± SEM at times after transplantation (***P ≤ 0.001; n = 4). (B) FACS analysis of bone marrow to determine the percentage of cells that were CD45.2+ after a competitive repopulation assay. (C) FACS analysis of LSK/FLT3– cells to determine the percentage of CD45.2+ cells that had repopulated the marrow 3 weeks after cBMT. (D) FACS analysis of bone marrow of control and Mx1-Cre:Hdac3–/– mice for GFP+ cells (for D: WT = 60% GFP+, null = 78% GFP+) that were LIN– and SCA1+ and c-KIT+. (E) Graphs of the numbers of colonies formed in methylcellulose at the indicated times from LTC-IC cultures of WT (open bars) and Hdac3–/– (filled bars) bone marrow cells, or WT cells treated with the indicated HDAC inhibitors (***P = 0.001, n = 3; *P = 0.013, week 3, n = 3; **P = 0.006, week 2; P = 0.002, week 3; P = 0.019, week 4, n = 3). Representative results from 2 separate experiments are shown. The numbers in each box are the relative percentage of the cells in the indicated gated population. Untr, untreated.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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