2. Academic Validation
  3. Evolutionary divergence in CTCF-mediated chromatin topology drives transcriptional innovation in humans

Evolutionary divergence in CTCF-mediated chromatin topology drives transcriptional innovation in humans

  • Nat Commun. 2025 Mar 26;16(1):2941. doi: 10.1038/s41467-025-58275-7.
Xia Wu # 1,  Dan Xiong # 1,  Rong Liu # 2 3,  Xingqiang Lai # 4,  Yuhan Tian # 1,  Ziying Xie 2,  Li Chen 2,  Lanqi Hu 2,  Jingjing Duan 2,  Xinyu Gao 2,  Xian Zeng 2,  Wei Dong 2,  Ting Xu 2,  Fang Fu 5,  Xin Yang 5,  Xinlai Cheng 6,  Dariusz Plewczynski 7 8,  Minji Kim 9,  Wenjun Xin 2,  Tianyun Wang 10 11 12,  Andy Peng Xiang 4,  Zhonghui Tang 13
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangdong, China.
  • 2 Zhongshan School of Medicine, Sun Yat-sen University, Guangdong, China.
  • 3 Institute of Precision Medicine, the First Affiliated Hospital, Sun Yat-Sen University, Guangdong, China.
  • 4 Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangdong, China.
  • 5 Department of Prenatal Diagnostic Center, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong, China.
  • 6 Buchmann Institute for Molecular Life Sciences, Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt, Germany.
  • 7 Laboratory of Bioinformatics and Computational Genomics, Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland.
  • 8 Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Warsaw, Poland.
  • 9 Department of Computational Medicine and Bioinformatics, University of Michigan, Michigan, MI, USA.
  • 10 Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University, Beijing, China.
  • 11 Neuroscience Research Institute, Peking University, Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Beijing, China.
  • 12 Autism Research Center, Peking University Health Science Center, Beijing, China.
  • 13 Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangdong, China. tangzhh99@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 40140405 DOI: 10.1038/s41467-025-58275-7
Abstract

Chromatin topology can impact gene regulation, but how evolutionary divergence in chromatin topology has shaped gene regulatory landscapes for distinctive human traits remains poorly understood. CTCF sites determine chromatin topology by forming domains and loops. Here, we show evolutionary divergence in CTCF-mediated chromatin topology at the domain and loop scales during primate evolution, elucidating distinct mechanisms for shaping regulatory landscapes. Human-specific divergent domains lead to a broad rewiring of transcriptional landscapes. Divergent CTCF loops concord with species-specific enhancer activity, influencing enhancer connectivity to target genes in a concordant yet constrained manner. Under this concordant mechanism, we establish the role of human-specific CTCF loops in shaping transcriptional isoform diversity, with functional implications for disease susceptibility. Furthermore, we validate the function of these human-specific CTCF loops using human forebrain organoids. This study advances our understanding of genetic evolution from the perspective of genome architecture.

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