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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 2

Inactivation of Hdac3 increases early stem and progenitor cells and blocks progression to the FLT3+ stage.

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Inactivation of Hdac3 increases early stem and progenitor cells and bloc...
FACS analysis of LIN– bone marrow to examine the (A) LSK population using SCA1 and c-KIT antibodies. (B) FACS analysis of LIN– and c-KIT+ cells in A using FcγR and CD34 antibodies to distinguish GMP, CMP, and MEP populations. (C) Further analysis of LSK population (small plots on the left) using FLT3 antibody and (D) CD34 antibody. Representative FACS plots from at least 5 mice are shown. In D, the shaded curves designate the control mice and the open curves are the null mice. (E) Immunophenotypic analysis of stem and MPP cells. Top panels show the scheme for the flow cytometric analysis and the markers used. Graph at right shows the actual number of cells per leg (STHSC, P= 0.0375; MPP1, P= 0.0069; MPP2, P= 0.04; LMPP, P= 0.0295). Numbers in each box indicate the relative percentage of the cells in the indicated gated population. *P < 0.05; **P < 0.007. LTHSC, long-term HSC; STHSC, short-term HSC.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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