Evolving insights on how cytosine methylation affects protein-DNA binding
Open accessAbstract
Many anecdotal observations exist of a regulatory effect of DNA methylation on gene expression. However, in general, the underlying mechanisms of this effect are poorly understood. In this review, we summarize what is currently known about how this important, but mysterious, epigenetic mark impacts cellular functions. Cytosine methylation can abrogate or enhance interactions with DNA-binding proteins, or it may have no effect, depending on the context. Despite being only a small chemical change, the addition of a methyl group to cytosine can affect base readout via hydrophobic contacts in the major groove and shape readout via electrostatic contacts in the minor groove. We discuss the recent discovery that CpG methylation increases DNase I cleavage at adjacent positions by an order of magnitude through altering the local 3D DNA shape and the possible implications of this structural insight for understanding the methylation sensitivity of transcription factors (TFs). Additionally, 5-methylcytosines change the stability of nucleosomes and, thus, affect the local chromatin structure and access of TFs to genomic DNA. Given these complexities, it seems unlikely that the influence of DNA methylation on protein-DNA binding can be captured in a small set of general rules. Hence, data-driven approaches may be essential to gain a better understanding of these mechanisms.
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Methylation has a profound impact on DNA structure and shape.
“Both in vitro DNase I digestion assays and structural studies indicate that methylation has a profound impact on DNA structure and shape”
From Transcription factors as readers and effectors of DNA methylation (2016) · cites this paper as [69]
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Flagged first, then by citations
Cited by
Sorted by citations
Transcription factors as readers and effectors of DNA methylation
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- Authors
- Dantas Machado, A. C., Zhou, T., Rao, S., Goel, P., Rastogi, C., Lazarovici, A., Bussemaker, H. J., & Rohs, R.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Rohs, R.
- Venue
- Briefings in Functional Genomics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-10-14
- Volume
- 14
- Issue
- 1
- Pages
- 61-73
- ISSN
- 2041-2647 (ISSN-L)
- 2041-2649
- 2041-2657
- PMC
- PMC4303714
- OpenAlex
- W2163964975
- Cited by
- 124
- References
- 114
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 16 · 2023: 8 · 2022: 13 · 2021: 7 · 2020: 8 · 2019: 15 · 2018: 12 · 2017: 10 · 2016: 13 · 2015: 7
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Briefings in Functional Genomics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Science Foundation (R01HG003008, 1413539)
- Alfred P. Sloan Foundation
- National Institutes of Health (U54-CA121852)
- National Human Genome Research Institute (R01HG003008)
- National Cancer Institute (U54CA121852)
- National Institute of General Medical Sciences (U01GM103804, T32GM082797, R01GM106056)
- 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 › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- DNA methylation, cytosine methylation, protein-DNA interactions, epigenetic regulation, CpG methylation, DNase I cleavage, nucleosome stability, chromatin structure, transcription factor binding, gene expression regulation
- MeSH terms
- Animals, Base Sequence, Cytosine, Humans, Models, Molecular, Nucleosomes, Protein Binding, Transcription Factors, DNA Methylation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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