Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b
Open accessAbstract
We have previously shown that the DNA methyltransferases Dnmt3a and Dnmt3b carry out de novo methylation of the mouse genome during early postimplantation development and of maternally imprinted genes in the oocyte. In the present study, we demonstrate that Dnmt3a and Dnmt3b are also essential for the stable inheritance, or "maintenance," of DNA methylation patterns. Inactivation of both Dnmt3a and Dnmt3b in embryonic stem (ES) cells results in progressive loss of methylation in various repeats and single-copy genes. Interestingly, introduction of the Dnmt3a, Dnmt3a2, and Dnmt3b1 isoforms back into highly demethylated mutant ES cells restores genomic methylation patterns; these isoforms appear to have both common and distinct DNA targets, but they all fail to restore the maternal methylation imprints. In contrast, overexpression of Dnmt1 and Dnmt3b3 failed to restore DNA methylation patterns due to their inability to catalyze de novo methylation in vivo. We also show that hypermethylation of genomic DNA by Dnmt3a and Dnmt3b is necessary for ES cells to form teratomas in nude mice. These results indicate that genomic methylation patterns are determined partly through differential expression of different Dnmt3a and Dnmt3b isoforms.
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DNMT3A encodes a de novo DNA methyltransferase enzyme responsible for establishing new DNA methylation patterns during development and stem cell fate decisions.
“Approximately 50% of all genetic variants in CH occur in the gene DNMT3A (6), which encodes a de novo DNA methyltransferase enzyme responsible for establishing new DNA methylation patterns during development and stem cell fate decisions (7,8).”
From <i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i> (2022) · cites this paper as [8]
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<i>Txnip</i> Enhances Fitness of <i>Dnmt3a</i> -Mutant Hematopoietic Stem Cells via <i>p21</i>
Zhang, C. R., Ostrander, E. L., Kukhar, O., Mallaney, C., Sun, J., Haussler, E., Celik, H., Koh, W. K., King, K. Y., Gontarz, P., et al. (2022) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0132 · Cited by 23 · see citing works
- Authors
- Chen, T., Ueda, Y., Dodge, J. E., Wang, Z., & Li, E.
- Affiliations
- Harvard University (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2003-08-01
- Volume
- 23
- Issue
- 16
- Pages
- 5594-5605
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC166327
- OpenAlex
- W2149790281
- Cited by
- 751
- References
- 1
- Citations by year
- 2026: 17 · 2025: 17 · 2024: 23 · 2023: 22 · 2022: 28 · 2021: 38 · 2020: 27 · 2019: 30 · 2018: 29 · 2017: 41 · 2016: 40 · 2015: 42 · 2014: 43 · 2013: 48 · 2012: 37
- FWCI
- 12.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Massachusetts General Hospital
- National Institutes of Health (2r01gm052106-06)
- Japan Society for the Promotion of Science
- National Cancer Institute (R01CA082389, CA 82389)
- National Institute of General Medical Sciences (GM52106)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- DNA methylation, DNA methyltransferases, DNMT3A, DNMT3B, DNMT3A2, DNMT1, genomic imprinting, embryonic stem cells, de novo methylation, teratoma formation, isoform specificity, mice
- MeSH terms
- DNA Methyltransferase 3A, DNA Methyltransferase 3B, Animals, Cell Differentiation, Crosses, Genetic, DNA, DNA (Cytosine-5-)-Methyltransferases, Exons, Genetic Vectors, Mice, Nude, Models, Genetic, Gene Deletion, DNA Methylation, Protein Isoforms, Amino Acid Motifs, Mice
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