Cited by 124Epigenetics and DNA MethylationGenomics and Chromatin DynamicsDNA and Nucleic Acid Chemistry

Evolving insights on how cytosine methylation affects protein-DNA binding

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Dantas Machado, A. C., Zhou, T., Rao, S., Goel, P., Rastogi, C., Lazarovici, A., Bussemaker, H. J., Rohs, R.·2015·Briefings in Functional Genomics

Abstract

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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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
Published
2014-10-14
Volume
14
Issue
1
Pages
61-73
ISSN
  • 2041-2647 (ISSN-L)
  • 2041-2649
  • 2041-2657
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
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

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