Cited by 6,143Epigenetics and DNA MethylationGenetic Syndromes and ImprintingGenomics and Chromatin Dynamics

DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development

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Okano, Masaki, Bell, Daphne W, Haber, Daniel A, Li, En·1999·Cell

Abstract

The establishment of DNA methylation patterns requires de novo methylation that occurs predominantly during early development and gametogenesis in mice. Here we demonstrate that two recently identified DNA methyltransferases, Dnmt3a and Dnmt3b, are essential for de novo methylation and for mouse development. Inactivation of both genes by gene targeting blocks de novo methylation in ES cells and early embryos, but it has no effect on maintenance of imprinted methylation patterns. Dnmt3a and Dnmt3b also exhibit nonoverlapping functions in development, with Dnmt3b specifically required for methylation of centromeric minor satellite repeats. Mutations of human DNMT3B are found in ICF syndrome, a developmental defect characterized by hypomethylation of pericentromeric repeats. Our results indicate that both Dnmt3a and Dnmt3b function as de novo methyltransferases that play important roles in normal development and disease.

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Crossref · 10.1016/s0092-8674(00)81656-6

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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).”
  • Global deletion of mouse Dnmt1, Dnmt3b, or both Dnmt3a + Dnmt3b results in midgestation lethality (GD 9.5-11.5), while deletion of only Dnmt3a produces severe growth retardation and lethality by 4 weeks of age.

    “Global deletion of mouse Dnmt1, Dnmt3b, or both Dnmt3a + Dnmt3b results in midgestation lethality [gestational day (GD) 9.5–11.5], while deletion of only Dnmt3a produces severe growth retardation and lethality by 4 weeks of age [ 70–72 ].”

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Authors
Okano, M., Bell, D. W., Haber, D. A., & Li, E.
Affiliations
Harvard University (US)
Corresponding author
Li, En
Venue
Cell
Publisher
Elsevier BV
Published
1999-10
Volume
99
Issue
3
Pages
247-257
ISSN
0092-8674 (ISSN-L)
OpenAlex
W2060446375
Cited by
6,143
References
45
Citations by year
2026: 157 · 2025: 206 · 2024: 230 · 2023: 260 · 2022: 248 · 2021: 279 · 2020: 301 · 2019: 295 · 2018: 315 · 2017: 315 · 2016: 340 · 2015: 341 · 2014: 331 · 2013: 315 · 2012: 289
FWCI
33.36
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (2r01gm052106-06)
  • 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 › Genomics and Chromatin Dynamics
Keywords
DNMT3A, DNMT3B, DNA methyltransferases, de novo methylation, mouse development, embryonic stem cells, centromeric satellite repeats, ICF syndrome, gene targeting
MeSH terms
DNA Methyltransferase 3A, DNA Methyltransferase 3B, Animals, Blastocyst, Centromere, Crosses, Genetic, DNA (Cytosine-5-)-Methyltransferases, Homozygote, Humans, Immunologic Deficiency Syndromes, Male, Mammals, Mice, Inbred C57BL, Repetitive Sequences, Nucleic Acid, Stem Cells, Mice, Knockout, DNA Methylation, Mice

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