title: Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells.
abstract: 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.
authors.affiliation: Division of Oncology, Section of Molecular Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA. Electronic address: gchallen@dom.wustl.edu.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Challen
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Deqiang
authors.initials: D
authors.lastname: Sun
authors.affiliation: Stem Cell and Regenerative Medicine Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Mayle
authors.affiliation: Stem Cell and Regenerative Medicine Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Mira
authors.initials: M
authors.lastname: Jeong
authors.affiliation: Stem Cell and Regenerative Medicine Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center for Aging, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rodriguez
authors.affiliation: Division of Oncology, Section of Molecular Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Cates
authors.initials: C
authors.lastname: Mallaney
authors.affiliation: Division of Oncology, Section of Molecular Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
authors.forename: Hamza
authors.initials: H
authors.lastname: Celik
authors.affiliation: Stem Cell and Regenerative Medicine Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Liubin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Stem Cell and Regenerative Medicine Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Cullen
authors.affiliation: Stem Cell and Regenerative Medicine Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Berg
authors.affiliation: Stem Cell and Regenerative Medicine Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Yayun
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Huffington Center for Aging, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Gretchen J
authors.initials: GJ
authors.lastname: Darlington
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; Stem Cell and Regenerative Medicine Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA. Electronic address: goodell@bcm.edu.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D018899:CpG Islands / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics; D000090205:DNA Methyltransferase 3A; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D007527:Isoenzymes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D051176:beta Catenin / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D007527:Isoenzymes; D051176:beta Catenin; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse