title: Dnmt3a is essential for hematopoietic stem cell differentiation.
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.
authors.affiliation: Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Challen
authors.forename: Deqiang
authors.initials: D
authors.lastname: Sun
authors.forename: Mira
authors.initials: M
authors.lastname: Jeong
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Berg
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
authors.forename: Aparna
authors.initials: A
authors.lastname: Vasanthakumar
authors.forename: Hongcang
authors.initials: H
authors.lastname: Gu
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Xi
authors.forename: Shoudan
authors.initials: S
authors.lastname: Liang
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.forename: Gretchen J
authors.initials: GJ
authors.lastname: Darlington
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A