Large conserved domains of low DNA methylation maintained by Dnmt3a
Open accessAbstract
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.
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Many alterations in genome methylation occurred in bivalent canyon sites that have been associated previously with developmentally important genes.
“many alterations in genome methylation occurred in bivalent canyon sites that have been associated previously with developmentally important genes (Jeong et al., 2014).”
From Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling (2021) · cites this paper as Jeong et al., 2014
Focal methylation alterations appear physiologically relevant.
“yet focal methylation alterations appear physiologically relevant (17,18,37,41).”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [41]
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- Authors
- Jeong, M., Sun, D., Luo, M., Huang, Y., Challen, G. A., Rodriguez, B., Zhang, X., Chavez, L., Wang, H., Hannah, R., Kim, S.-B., Yang, L., Ko, M., Chen, R., Göttgens, B., Lee, J.-S., Gunaratne, P., Godley, L. A., Darlington, G. J., Rao, A., Li, W., & Goodell, M. A.
- Affiliations
- Baylor College of Medicine (US)
- La Jolla Institute for Immunology (US)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- The University of Texas MD Anderson Cancer Center (US)
- University of Chicago (US)
- Corresponding author
- Li, Wei
- Goodell, Margaret A
- ORCID
- Venue
- Nature Genetics
- Published
- 2013-11-24
- Volume
- 46
- Issue
- 1
- Pages
- 17-23
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC3920905
- OpenAlex
- W2015493376
- Cited by
- 324
- References
- 2
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 15 · 2023: 24 · 2022: 18 · 2021: 32 · 2020: 22 · 2019: 23 · 2018: 22 · 2017: 28 · 2016: 40 · 2015: 34 · 2014: 38 · 2013: 1
- FWCI
- 16.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- Wellcome Trust (079249, 100140)
- Cancer Research UK (12765)
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (G0900729/1)
- Medical Research Council (MC_PC_12009)
- Biotechnology and Biological Sciences Research Council (BB/I00050X/1)
- National Institute on Aging (AG036562, RC2AG036562)
- National Human Genome Research Institute (R01HG007538)
- National Cancer Institute (R01CA151535, CA151535, CA125123, CA126752, P30CA125123, P50CA126752)
- National Institute of Allergy and Infectious Diseases (T32AI007495, AI07495)
- National Institute of Diabetes and Digestive and Kidney Diseases (K99DK084259, DK084259, DK092883, R56DK092883, R00DK084259, R01DK092883)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD065812)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- DNA methylation, 5-hydroxymethylcytosine, DNMT3A, hematopoietic stem cells, conserved domains, histone modifications, leukemia, hematopoiesis, epigenetic regulation, 5-methylcytosine
- MeSH terms
- DNA Methyltransferase 3A, Animals, Base Sequence, Cytosine, DNA (Cytosine-5-)-Methyltransferases, Gene Expression Regulation, Hematopoietic Stem Cells, Histones, Humans, Leukemia, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Conserved Sequence, CpG Islands, DNA Methylation, Databases, Genetic, Epigenesis, Genetic, 5-Methylcytosine, Mice
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