Dnmt3a is essential for hematopoietic stem cell differentiation

Grant A. Challen, Deqiang Sun, Mira Jeong, Min Luo, Jaroslav Jelinek, Jonathan S. Berg, Christoph Bock, Aparna Vasanthakumar, Hongcang Gu, Yuanxin Xi, Shoudan Liang, Yue Lu, Gretchen J. Darlington, Alexander Meissner, Jean Pierre J. Issa, Lucy A. Godley, Wei Li, Margaret A. Goodell

Research output: Contribution to journalArticlepeer-review

749 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)23-31
Number of pages9
JournalNature Genetics
Volume44
Issue number1
DOIs
StatePublished - Jan 2012

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