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Cell Stem Cell. 2014 Sep 4;15(3):350-364. doi: 10.1016/j.stem.2014.06.018. Epub 2014 Aug 14.

Dnmt3a and Dnmt3b have overlapping and distinct functions in hematopoietic stem cells.

Author information

1
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.
2
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.
3
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.
4
Stem Cell and Regenerative Medicine Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
5
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.
6
Division of Oncology, Section of Molecular Oncology, Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO 63110, USA.
7
Huffington Center for Aging, Baylor College of Medicine, Houston, TX 77030, USA.
8
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.

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.

PMID:
25130491
PMCID:
PMC4163922
DOI:
10.1016/j.stem.2014.06.018
[Indexed for MEDLINE]
Free PMC Article

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