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Nat Genet. 2014 Jan;46(1):17-23. doi: 10.1038/ng.2836. Epub 2013 Nov 24.

Large conserved domains of low DNA methylation maintained by Dnmt3a.

Author information

1
1] Stem Cells and Regenerative Medicine Center, Department of Pediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2].
2
1] Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. [2].
3
Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
4
Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
5
Stem Cells and Regenerative Medicine Center, Department of Pediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
6
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
7
Department of Hematology, Cambridge Institute for Medical Research and Wellcome Trust and Medical Research Council Cambridge Stem Cell Institute, Cambridge University, Cambridge, UK.
8
Department of Systems Biology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
9
1] Department of Pathology, Baylor College of Medicine, Houston, Texas, USA. [2] Department of Biology & Biochemistry, University of Houston, Houston, Texas, USA.
10
Department of Medicine, University of Chicago, Chicago, Illinois, USA.
11
Huffington Center for Aging, Baylor College of Medicine, Houston, Texas, USA.

Abstract

Gains and losses in DNA methylation are prominent features of mammalian cell types. To gain insight into the mechanisms that promote shifts in DNA methylation and contribute to changes in cell fate, including malignant transformation, we performed genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. We discovered extended regions of low methylation (canyons) that span conserved domains frequently containing transcription factors and are distinct from CpG islands and shores. About half of the genes in these methylation canyons are coated with repressive histone marks, whereas the remainder are covered by activating histone marks and are highly expressed in hematopoietic stem cells (HSCs). Canyon borders are demarked by 5-hydroxymethylcytosine and become eroded in the absence of DNA methyltransferase 3a (Dnmt3a). Genes dysregulated in human leukemias are enriched for canyon-associated genes. The new epigenetic landscape we describe may provide a mechanism for the regulation of hematopoiesis and may contribute to leukemia development.

PMID:
24270360
PMCID:
PMC3920905
DOI:
10.1038/ng.2836
[Indexed for MEDLINE]
Free PMC Article

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