Cited by 1,257Epigenetics and DNA MethylationGenomics and Chromatin DynamicsDNA and Nucleic Acid Chemistry

Impact of cytosine methylation on DNA binding specificities of human transcription factors

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Yin, Yimeng, Morgunova, Ekaterina, Jolma, Arttu, Kaasinen, Eevi, Sahu, Biswajyoti, Khund-Sayeed, Syed, Das, Pratyush K., Kivioja, Teemu +11 more·2017·Science

Abstract

Positives and negatives of methylated CpG: When the DNA bases cytosine and guanine are next to each other, a methyl group is generally added to the pyrimidine, generating a mCpG dinucleotide. This modification alters DNA structure but can also affect function by inhibiting transcription factor (TF) binding. Yin et al. systematically analyzed the effect of CpG methylation on the binding of 542 human TFs (see the Perspective by Hughes and Lambert). In addition to inhibiting binding of some TFs, they found that mCpGs can promote binding of others, particularly TFs involved in development, such as homeodomain proteins. Science , this issue p. eaaj2239 ; see also p. 489

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Crossref · 10.1126/science.aaj2239

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  • The HNF4A binding motif does not contain a CG which can be methylated, thus making it a methylation-insensitive TF.

    “Of interest, the HNF4A binding motif does not contain a CG which can be methylated, thus making it a methylation-insensitive TF (11, 17).”

    From Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver (2019) · cites this paper as [17]

    The sections “CpG methylation has a major effect on TF-DNA binding” and “Binding of most TFs can be affected by CpG methylation” say that TFs whose recognition sequences lack CpG are not affected by CpG methylation. Our copy does not identify HNF4A as one of those TFs or establish that its binding motif lacks CG, so the HNF4A-specific claim is not verified. (LLM, conf=0.82)

    Experimental — accuracy not yet measured
  • Many transcription factors, including several ETS family members, display reduced binding affinities to DNA motifs containing methylated cytosine residues.

    “Although many TF, including several members of the ETS family, display reduced binding affinities to DNA motifs containing methylated cytosine residues (44)”
  • Hypermethylation of DMR_394 may disrupt binding of regulatory proteins and adversely affect the organization and regulation of nearby genes.

    “Given that the affinity of many transcription factors, including CTCF31, is negatively impacted by methylation of their binding sites32, it is possible that hypermethylation of DMR_394 disrupts binding of regulatory proteins and adversely affects the organization and regulation of genes nearby.”
  • 5mC is associated with gene repression and can disrupt the binding of many TFs.

    “DNA methylation (5-methylcytosine or 5mC) is associated with gene repression (16) and can disrupt the binding of many TFs (17, 18).”
  • Certain interactions between transcription factors and low-affinity binding sites can be enhanced by 5mC.

    “These studies unexpectedly uncovered that certain interactions between TFs and low affinity binding sites can be enhanced by the presence of 5mC.”

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Authors
Yin, Y., Morgunova, E., Jolma, A., Kaasinen, E., Sahu, B., Khund-Sayeed, S., Das, P. K., Kivioja, T., Dave, K., Zhong, F., Nitta, K. R., Taipale, M., Popov, A., Ginno, P. A., Domcke, S., Yan, J., Schübeler, D., Vinson, C., & Taipale, J.
Affiliations
  • Karolinska Institutet (SE)
  • University of Helsinki (FI)
  • National Institutes of Health (US)
  • European Synchrotron Radiation Facility (FR)
  • Friedrich Miescher Institute (CH)
  • University of Basel (CH)
Corresponding author
Taipale, Jussi
Venue
Science
Published
2017-05-05
Volume
356
Issue
6337
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2610903912
Cited by
1,257
References
97
Citations by year
2026: 92 · 2025: 138 · 2024: 148 · 2023: 159 · 2022: 166 · 2021: 150 · 2020: 125 · 2019: 125 · 2018: 113 · 2017: 37 · 2016: 2
FWCI
44.66
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Academy of Finland Center of Excellence in Cancer Genetics
  • European Research Area SynBio
  • Center for Innovative Medicine at Karolinska Institutet
  • Knut and Alice Wallenberg Foundation
  • Göran Gustafsson Foundation
  • Vetenskapsrådet
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
cytosine methylation, CpG methylation, transcription factor binding specificity, DNA methylation, homeodomain transcription factor, 5-methylcytosine, hydrophobic interactions, epigenetic regulation, gene regulatory elements
MeSH terms
Protein Domains, Cytosine, DNA, Humans, Protein Binding, Transcription Factors, Dinucleoside Phosphates, Genome, Human, CpG Islands, DNA Methylation, Epigenesis, Genetic, SELEX Aptamer Technique

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