Cited by 37Epigenetics and DNA MethylationDNA and Nucleic Acid ChemistryGenomics and Chromatin Dynamics

Differential sensitivity to methylated DNA by ETS-family transcription factors is intrinsically encoded in their DNA-binding domains

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Stephens, Dominique C., Poon, Gregory M. K.·2016·Nucleic Acids Research

Abstract

Transactivation by the ETS family of transcription factors, whose members share structurally conserved DNA-binding domains, is variably sensitive to methylation of their target genes. The mechanism by which DNA methylation controls ETS proteins remains poorly understood. Uncertainly also pervades the effects of hemi-methylated DNA, which occurs following DNA replication and in response to hypomethylating agents, on site recognition by ETS proteins. To address these questions, we measured the affinities of two sequence-divergent ETS homologs, PU.1 and Ets-1, to DNA sites harboring a hemi- and fully methylated CpG dinucleotide. While the two proteins bound unmethylated DNA with indistinguishable affinity, their affinities to methylated DNA are markedly heterogeneous and exhibit major energetic coupling between the two CpG methylcytosines. Analysis of simulated DNA and existing co-crystal structures revealed that hemi-methylation induced non-local backbone and groove geometries that were not conserved in the fully methylated state. Indirect readout of these perturbations was differentially achieved by the two ETS homologs, with the distinctive interfacial hydration in PU.1/DNA binding moderating the inhibitory effects of DNA methylation on binding. This data established a biophysical basis for the pioneering properties associated with PU.1, which robustly bound fully methylated DNA, but not Ets-1, which was substantially inhibited.

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Authors
Stephens, D. C., & Poon, G. M. K.
Affiliations
Georgia State University (US)
Corresponding author
Poon, Gregory M. K.
Venue
Nucleic Acids Research
Published
2016-06-07
Volume
44
Issue
18
Pages
8671-8681
ISSN
  • 0305-1048 (ISSN-L)
  • 1362-4962
OpenAlex
W2416365174
Cited by
37
References
63
Citations by year
2026: 3 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 2 · 2018: 6 · 2017: 7
FWCI
2.60
Type
journal article
Language
en
Open access
Locations
  • Nucleic Acids Research (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
National Heart, Lung, and Blood Institute (R21HL129063)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
ETS transcription factors, DNA methylation, CpG, PU.1, ETS1, DNA binding affinity, DNA-binding domain, pioneer transcription factors, DNA replication, interfacial hydration, transcriptional repression
MeSH terms
Protein Domains, Proto-Oncogene Protein Spi-1, Animals, Binding Sites, DNA, Nucleic Acid Conformation, Protein Binding, Proto-Oncogene Proteins, Thermodynamics, Trans-Activators, CpG Islands, DNA Methylation, Principal Component Analysis, 5-Methylcytosine, Proto-Oncogene Proteins c-ets, Mice

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