NuRD-enabled CTCF-TET crosstalk orchestrates epigenome reprogramming and genome architecture

  • Mol Cell. 2026 Jul 2;86(13):2617-2634.e11. doi: 10.1016/j.molcel.2026.05.010.
Wenju Sun  1 ,  Nan Wu  2 ,  Minhui Xia  3 ,  Yilin Pan  4 ,  Meishuo Liu  5 ,  Shaorong Fan  6 ,  Jueheng Wang  3 ,  Yitian Zeng  5 ,  Ligang Fan  6 ,  Jie Chen  4 ,  Guopan Liu  4 ,  Huanyu Yan  7 ,  Yunjiang Qiu  8 ,  Yang Xie  8 ,  Zenan Jiang  6 ,  Fulin Chen  1 ,  Yimeng Yin  9 ,  Jilin Zhang  10 ,  Lei Li  11 ,  Wei Xie  5 ,  Haifeng Wang  5 ,  Liang Zhang  12 ,  Miao Yu  13 ,  Xi Wang  14 ,  Jian Yan  15
Affiliations
  • 1. School of Medicine, Northwest University, Xi'an 710069, China.
  • 2. School of Medicine, Northwest University, Xi'an 710069, China; Tung Biomedical Sciences Centre, Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Hong Kong, China; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 3. State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, Shanghai 200438, China.
  • 4. Tung Biomedical Sciences Centre, Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Hong Kong, China.
  • 5. School of Life Sciences, Tsinghua-Peking Joint Center for Life Sciences, Center for Synthetic and Systems Biology, State Key Laboratory of Complex, Severe, and Rare Diseases, Tsinghua University, Beijing 100084, China.
  • 6. School of Medicine, Northwest University, Xi'an 710069, China; Tung Biomedical Sciences Centre, Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Hong Kong, China.
  • 7. State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Prenatal Diagnosis of the First Affiliated Hospital, Department of Urology of the Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China.
  • 8. Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093, USA.
  • 9. State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200333, China.
  • 10. Tung Biomedical Sciences Centre, Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Hong Kong, China; Department of Precision Diagnostic and Therapeutic Technology, The City University of Hong Kong Shenzhen Research Institute, Shenzhen 518057, China.
  • 11. Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
  • 12. Tung Biomedical Sciences Centre, Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Hong Kong, China; Department of Precision Diagnostic and Therapeutic Technology, The City University of Hong Kong Shenzhen Research Institute, Shenzhen 518057, China. Electronic address: [email protected].
  • 13. State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, Shanghai 200438, China. Electronic address: [email protected].
  • 14. State Key Laboratory of Reproductive Medicine and Offspring Health, Department of Prenatal Diagnosis of the First Affiliated Hospital, Department of Urology of the Second Affiliated Hospital, Nanjing Medical University, Nanjing 211166, China. Electronic address: [email protected].
  • 15. School of Medicine, Northwest University, Xi'an 710069, China; Tung Biomedical Sciences Centre, Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Hong Kong, China; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China; Department of Precision Diagnostic and Therapeutic Technology, The City University of Hong Kong Shenzhen Research Institute, Shenzhen 518057, China. Electronic address: [email protected].
PMID: 42225060 DOI: 10.1016/j.molcel.2026.05.010
Abstract

CCCTC-binding factor (CTCF) is an evolutionarily conserved transcription factor with diverse regulatory roles. Its binding sites exhibit highly ordered nucleosomes and DNA hypomethylation, but how this epigenetic landscape is established remains unclear. In this study, we develop a GpC methylation-assisted tracing (G-MAT) approach to investigate the interplay between DNA methylation and CTCF binding at a base-pair resolution, which reveals that CTCF-chromatin interaction frequently coincides with methylated DNA, which is likely mediated by the nucleosome remodeling and deacetylase (NuRD) complex. We show that NuRD is indispensable for CTCF's chromatin binding, emerging as a regulator of high-order genome architecture. Mechanistically, NuRD facilitates CTCF to interact with TET methylcytosine dioxygenase to maintain adjacent DNA hypomethylation, which is essential for activation of nearby genes. Notably, embryonic stem cells lacking NuRD exhibit impaired lineage commitment. Together, our study unravels a mechanism that elucidates the crosstalk between CTCF binding and the epigenome, with NuRD playing a crucial role as a mediator.

Keywords
CTCF; DNA methylation; NuRD; TET; genome architecture; stem cell differentiation.
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