title: Large conserved domains of low DNA methylation maintained by Dnmt3a.
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.
authors.affiliation: 1] Stem Cells and Regenerative Medicine Center, Department of Pediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2].
authors.forename: Mira
authors.initials: M
authors.lastname: Jeong
authors.affiliation: 1] Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. [2].
authors.forename: Deqiang
authors.initials: D
authors.lastname: Sun
authors.affiliation: 1] Stem Cells and Regenerative Medicine Center, Department of Pediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2].
authors.forename: Min
authors.initials: M
authors.lastname: Luo
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: 1] Stem Cells and Regenerative Medicine Center, Department of Pediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2].
authors.forename: Grant A
authors.initials: GA
authors.lastname: Challen
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rodriguez
authors.affiliation: Stem Cells and Regenerative Medicine Center, Department of Pediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Lukas
authors.initials: L
authors.lastname: Chavez
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Hematology, Cambridge Institute for Medical Research and Wellcome Trust and Medical Research Council Cambridge Stem Cell Institute, Cambridge University, Cambridge, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Hannah
authors.affiliation: Department of Systems Biology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Stem Cells and Regenerative Medicine Center, Department of Pediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Liubin
authors.initials: L
authors.lastname: Yang
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Myunggon
authors.initials: M
authors.lastname: Ko
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Chen
authors.affiliation: Department of Hematology, Cambridge Institute for Medical Research and Wellcome Trust and Medical Research Council Cambridge Stem Cell Institute, Cambridge University, Cambridge, UK.
authors.forename: Berthold
authors.identifier: 0000000163025705
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: Department of Systems Biology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: 1] Department of Pathology, Baylor College of Medicine, Houston, Texas, USA. [2] Department of Biology & Biochemistry, University of Houston, Houston, Texas, USA.
authors.forename: Preethi
authors.initials: P
authors.lastname: Gunaratne
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois, USA.
authors.forename: Lucy A
authors.initials: LA
authors.lastname: Godley
authors.affiliation: Huffington Center for Aging, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Gretchen J
authors.initials: GJ
authors.lastname: Darlington
authors.affiliation: Division of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
authors.affiliation: 1] Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA. [2].
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: 1] Stem Cells and Regenerative Medicine Center, Department of Pediatrics and Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA. [2].
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Goodell
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence; D018899:CpG Islands; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D030541:Databases, Genetic; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains
chemical_list: C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D006657:Histones; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A