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

Xia Wu, Dan Xiong, Rong Liu, Xingqiang Lai, Yuhan Tian, Ziying Xie, Li Chen, Lanqi Hu, Jingjing Duan, Xinyu Gao, Xian Zeng, Wei Dong, Ting Xu, Fang Fu, Xin Yang, Xinlai Cheng, Dariusz Plewczynski, Minji Kim, Wenjun Xin, Tianyun Wang, Andy Peng Xiang and Zhonghui Tang ()
Additional contact information
Xia Wu: Sun Yat-sen University
Dan Xiong: Sun Yat-sen University
Rong Liu: Sun Yat-sen University
Xingqiang Lai: Sun Yat-Sen University
Yuhan Tian: Sun Yat-sen University
Ziying Xie: Sun Yat-sen University
Li Chen: Sun Yat-sen University
Lanqi Hu: Sun Yat-sen University
Jingjing Duan: Sun Yat-sen University
Xinyu Gao: Sun Yat-sen University
Xian Zeng: Sun Yat-sen University
Wei Dong: Sun Yat-sen University
Ting Xu: Sun Yat-sen University
Fang Fu: Guangzhou Medical University
Xin Yang: Guangzhou Medical University
Xinlai Cheng: Goethe-University Frankfurt
Dariusz Plewczynski: Warsaw University of Technology
Minji Kim: University of Michigan
Wenjun Xin: Sun Yat-sen University
Tianyun Wang: Peking University
Andy Peng Xiang: Sun Yat-Sen University
Zhonghui Tang: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-33

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58275-7

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