TY - JOUR
T1 - Dnmt3a is essential for hematopoietic stem cell differentiation
AU - Challen, Grant A.
AU - Sun, Deqiang
AU - Jeong, Mira
AU - Luo, Min
AU - Jelinek, Jaroslav
AU - Berg, Jonathan S.
AU - Bock, Christoph
AU - Vasanthakumar, Aparna
AU - Gu, Hongcang
AU - Xi, Yuanxin
AU - Liang, Shoudan
AU - Lu, Yue
AU - Darlington, Gretchen J.
AU - Meissner, Alexander
AU - Issa, Jean Pierre J.
AU - Godley, Lucy A.
AU - Li, Wei
AU - Goodell, Margaret A.
N1 - Funding Information:
The authors would like to thank all members of the Goodell laboratory for scientific advice, A. Rosen, Y. Zheng and L. Yang for mouse management and technical support, C. Threeton for flow cytometry, L. White (microarray core) and A. Gnirke for assistance with the RRBS technique. G.A.C. was supported by a grant from the US National Institutes of Health (NIH K99 DK084259-01A1) and is an American Society of Hematology Scholar. This work was also supported by NIH grants (AG036562, HL086223, CA100632, CA129831, P50CA126752, DK092883, CA125123 and DK58192), the Ellison foundation, the American Heart Association (CPRIT grant RP110028) and the Functional Genomics Core (P30 DK056338).
PY - 2012/1
Y1 - 2012/1
N2 - Loss of the de novo DNA methyltransferases Dnmt3a and Dnmt3b in embryonic stem cells obstructs differentiation; however, the role of these enzymes in somatic stem cells is largely unknown. Using conditional ablation, we show that Dnmt3a loss progressively impairs hematopoietic stem cell (HSC) differentiation over serial transplantation, while simultaneously expanding HSC numbers in the bone marrow. Dnmt3a-null HSCs show both increased and decreased methylation at distinct loci, including substantial CpG island hypermethylation. Dnmt3a-null HSCs upregulate HSC multipotency genes and downregulate differentiation factors, and their progeny exhibit global hypomethylation and incomplete repression of HSC-specific genes. These data establish Dnmt3a as a critical participant in the epigenetic silencing of HSC regulatory genes, thereby enabling efficient differentiation.
AB - Loss of the de novo DNA methyltransferases Dnmt3a and Dnmt3b in embryonic stem cells obstructs differentiation; however, the role of these enzymes in somatic stem cells is largely unknown. Using conditional ablation, we show that Dnmt3a loss progressively impairs hematopoietic stem cell (HSC) differentiation over serial transplantation, while simultaneously expanding HSC numbers in the bone marrow. Dnmt3a-null HSCs show both increased and decreased methylation at distinct loci, including substantial CpG island hypermethylation. Dnmt3a-null HSCs upregulate HSC multipotency genes and downregulate differentiation factors, and their progeny exhibit global hypomethylation and incomplete repression of HSC-specific genes. These data establish Dnmt3a as a critical participant in the epigenetic silencing of HSC regulatory genes, thereby enabling efficient differentiation.
UR - http://www.scopus.com/inward/record.url?scp=84555207349&partnerID=8YFLogxK
U2 - 10.1038/ng.1009
DO - 10.1038/ng.1009
M3 - Article
C2 - 22138693
AN - SCOPUS:84555207349
SN - 1061-4036
VL - 44
SP - 23
EP - 31
JO - Nature Genetics
JF - Nature Genetics
IS - 1
ER -