HDAC3 is essential for DNA replication in hematopoietic progenitor cells.
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.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Alyssa R
AR
Summers
Melissa A
MA
Fischer
Kristy R
KR
Stengel
Yue
Y
Zhao
Jonathan F
JF
Kaiser
Christina E
CE
Wells
Aubrey
A
Hunt
Srividya
S
Bhaskara
Jessica W
JW
Luzwick
Shilpa
S
Sampathi
Xi
X
Chen
Mary Ann
MA
Thompson
David
D
Cortez
Scott W
SW
Hiebert
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004261:DNA Replication; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000502:physiology; D006655:Histone Deacetylases / Q000502:physiology*; D038041:Lymphopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016196:S Phase; D013154:Spleen / Q000473:pathology; D059467:Transcriptome; D000099186:Histone Deacetylase 3
D006655:Histone Deacetylases; D000099186:Histone Deacetylase 3