Dnmt3a and Dnmt3b Have Overlapping and Distinct Functions in Hematopoietic Stem Cells

• DOI: 10.1016/j.stem.2014.06.018
• Publication Date: 2014-08-14T16:45:54Z
• Authors: Grant A. Challen; Deqiang Sun; Allison Mayle; Mira Jeong; Min Luo; Benjamin Rodriguez; Cates Mallaney; Hamza Celik; Liubin Yang; Zheng Xia; Sean Cullen; Jonathan Berg; Yayun Zheng; Gretchen J. Darli...; Wei Li; Margaret A. Goodell
• Keywords: Mice, Knockout; DNA Methyltransferase 3B; 0303 health sciences; Gene Expression Regulation, Developmental; Apoptosis; Cell Differentiation; Cell Biology; DNA Methylation; Hematopoietic Stem Cells; DNA Methyltransferase 3A; Epigenesis, Genetic; Isoenzymes; Mice, Inbred C57BL; 03 medical and health sciences; Neoplasms; Genetics; Molecular Medicine; Animals; CpG Islands; Gene Regulatory Networks; DNA (Cytosine-5-)-Methyltransferases; beta Catenin; Cell Proliferation

Epigenetic regulation of hematopoietic stem cells (HSCs) ensures lifelong production of blood and bone marrow. Recently, we reported that loss of de novo DNA methyltransferase Dnmt3a results in HSC expansion and impaired differentiation. Here, we report conditional inactivation of Dnmt3b in HSCs either alone or combined with Dnmt3a deletion. Combined loss of Dnmt3a and Dnmt3b was synergistic, resulting in enhanced HSC self-renewal and a more severe block in differentiation than in Dnmt3a-null cells, whereas loss of Dnmt3b resulted in a mild phenotype. Although the predominant Dnmt3b isoform in adult HSCs is catalytically inactive, its residual activity in Dnmt3a-null HSCs can drive some differentiation and generates paradoxical hypermethylation of CpG islands. Dnmt3a/Dnmt3b-null HSCs displayed activated β-catenin signaling, partly accounting for the differentiation block. These data demonstrate distinct roles for Dnmt3b in HSC differentiation and provide insights into complementary de novo methylation patterns governing regulation of HSC fate decisions.