DNA methylation presents distinct binding sites for human transcription factors

Shaohui Hu, Jun Wan, Yijing Su, Qifeng Song, Yaxue Zeng, Ha Nam Nguyen, Jaehoon Shin, Eric Cox, Hee-Sool Rho, Crystal Woodard, Shuli Xia, Shuang Liu, Huibin Lyu, Guo Li Ming, Herschel Wade, Hongjun Song, Jiang Qian, Heng Zhu

Research output: Contribution to journalArticlepeer-review

201 Scopus citations


DNA methylation, especially CpG methylation at promoter regions, has been generally considered as a potent epigenetic modification that prohibits transcription factor (TF) recruitment, resulting in transcription suppression. Here, we used a protein microarray-based approach to systematically survey the entire human TF family and found numerous purified TFs with methylated CpG (mCpG)-dependent DNA-binding activities. Interestingly, some TFs exhibit specific binding activity to methylated and unmethylated DNA motifs of distinct sequences. To elucidate the underlying mechanism, we focused on Kruppel-like factor 4 (KLF4), and decoupled its mCpG- and CpG-binding activities via site-directed mutagenesis. Furthermore, KLF4 binds specific methylated or unmethylated motifs in human embryonic stem cells in vivo. Our study suggests that mCpG-dependent TF binding activity is a widespread phenomenon and provides a new framework to understand the role and mechanism of TFs in epigenetic regulation of gene transcription.

Original languageEnglish (US)
Article numbere00726
Issue number2
StatePublished - Sep 3 2013

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)


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