Epigenetic regulation of hematopoiesis by DNA methylation
Aniket V Gore,
Brett Athans,
James R Iben,
Kristin Johnson,
Valya Russanova,
Daniel Castranova,
Van N Pham,
Matthew G Butler,
Lisa Williams-Simons,
James T Nichols,
Erica Bresciani,
Bejamin Feldman,
Charles B Kimmel,
Paul P Liu,
Brant M Weinstein
Affiliations
Aniket V Gore
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
Brett Athans
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
James R Iben
Program in Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
Kristin Johnson
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
Valya Russanova
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
Daniel Castranova
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
Van N Pham
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
Matthew G Butler
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
Lisa Williams-Simons
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
James T Nichols
Institute of Neuroscience, University of Oregon, Eugene, United States
Erica Bresciani
Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States
Bejamin Feldman
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
Charles B Kimmel
Institute of Neuroscience, University of Oregon, Eugene, United States
Paul P Liu
Oncogenesis and Development Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, United States
Brant M Weinstein
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States
During embryonic development, cell type-specific transcription factors promote cell identities, while epigenetic modifications are thought to contribute to maintain these cell fates. Our understanding of how genetic and epigenetic modes of regulation work together to establish and maintain cellular identity is still limited, however. Here, we show that DNA methyltransferase 3bb.1 (dnmt3bb.1) is essential for maintenance of hematopoietic stem and progenitor cell (HSPC) fate as part of an early Notch-runx1-cmyb HSPC specification pathway in the zebrafish. Dnmt3bb.1 is expressed in HSPC downstream from Notch1 and runx1, and loss of Dnmt3bb.1 activity leads to reduced cmyb locus methylation, reduced cmyb expression, and gradual reduction in HSPCs. Ectopic overexpression of dnmt3bb.1 in non-hematopoietic cells is sufficient to methylate the cmyb locus, promote cmyb expression, and promote hematopoietic development. Our results reveal an epigenetic mechanism supporting the maintenance of hematopoietic cell fate via DNA methylation-mediated perdurance of a key transcription factor in HSPCs.
