Nucleosomes containing methylated DNA stabilize DNA methyltransferases 3A/3B and ensure faithful epigenetic inheritance
Open accessAbstract
How epigenetic information is propagated during somatic cell divisions is still unclear but is absolutely critical for preserving gene expression patterns and cellular identity. Here we show an unanticipated mechanism for inheritance of DNA methylation patterns where the epigenetic mark not only recruits the catalyzing enzyme but also regulates the protein level, i.e. the enzymatic product (5-methylcytosine) determines the level of the methylase, thus forming a novel homeostatic inheritance system. Nucleosomes containing methylated DNA stabilize de novo DNA methyltransferases, DNMT3A/3B, allowing little free DNMT3A/3B enzymes to exist in the nucleus. Stabilization of DNMT3A/3B on nucleosomes in methylated regions further promotes propagation of DNA methylation. However, reduction of cellular DNA methylation levels creating more potential CpG substrates counter-intuitively results in a dramatic decrease of DNMT3A/3B proteins due to diminished nucleosome binding and subsequent degradation of the unstable free proteins. These data show an unexpected self-regulatory inheritance mechanism that not only ensures somatic propagation of methylated states by DNMT1 and DNMT3A/3B enzymes but also prevents aberrant de novo methylation by causing degradation of free DNMT3A/3B enzymes.
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DNA methylation can also enhance gene expression through more complicated mechanisms such as methylation of CTCF binding sites and/or intronic regions.
“However, DNA methylation also enhances gene expression through more complicated mechanisms such as the methylation of CCCTC-binding factor (CTCF) binding sites and/or intronic regions (45–49).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [46]
The Introduction describes DNA methylation as a gene-silencing mechanism. The Discussion mentions CTCF as antagonistic to methylation, but does not say that methylating CTCF binding sites enhances expression. Searches for CTCF-site methylation and intronic methylation found no passage addressing the claimed expression-enhancing mechanisms; the copy does not rule out their occurrence elsewhere. (LLM, conf=0.72)
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Self-citation
- Authors
- Sharma, S., De Carvalho, D. D., Jeong, S., Jones, P. A., & Liang, G.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Jones, Peter A.
- Liang, Gangning
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-02-03
- Volume
- 7
- Issue
- 2
- Pages
- e1001286
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3033376
- OpenAlex
- W1979413690
- Cited by
- 119
- References
- 56
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 4 · 2017: 11 · 2016: 12 · 2015: 13 · 2014: 10 · 2013: 10 · 2012: 17
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, other-oa)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Cancer Institute (R01CA124518, CA082422, R37CA082422)
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- DNA methylation, epigenetic inheritance, DNMT3A, DNMT3B, nucleosome binding, protein stabilization, protein degradation, 5-methylcytosine, de novo methylation, DNMT1, somatic cell division, CpG sites
- MeSH terms
- DNA (Cytosine-5-)-Methyltransferase 1, DNA Methyltransferase 3A, DNA Methyltransferase 3B, DNA (Cytosine-5-)-Methyltransferases, Enzyme Stability, Genetic Vectors, Humans, Nucleosomes, CpG Islands, DNA Methylation, Gene Silencing, Gene Expression Profiling, Epigenesis, Genetic, 5-Methylcytosine, HCT116 Cells
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