An alternative CTCF isoform antagonizes canonical CTCF occupancy and changes chromatin architecture to promote apoptosis

Jiao Li, Kaimeng Huang, Gongcheng Hu, Isaac A. Babarinde, Yaoyi Li, Xiaotao Dong, Yu-Sheng Chen, Liping Shang, Wenjing Guo, Junwei Wang, Zhaoming Chen, Andrew P. Hutchins, Yun-Gui Yang and Hongjie Yao ()
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Jiao Li: Guangzhou Medical University
Kaimeng Huang: Guangzhou Medical University
Gongcheng Hu: Guangzhou Medical University
Isaac A. Babarinde: Southern University of Science and Technology
Yaoyi Li: Guangzhou Medical University
Xiaotao Dong: Guangzhou Medical University
Yu-Sheng Chen: Chinese Academy of Sciences
Liping Shang: Guangzhou Medical University
Wenjing Guo: Guangzhou Medical University
Junwei Wang: Guangzhou Medical University
Zhaoming Chen: Guangzhou Medical University
Andrew P. Hutchins: Southern University of Science and Technology
Yun-Gui Yang: University of Chinese Academy of Sciences
Hongjie Yao: Guangzhou Medical University

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract CTCF plays key roles in gene regulation, chromatin insulation, imprinting, X chromosome inactivation and organizing the higher-order chromatin architecture of mammalian genomes. Previous studies have mainly focused on the roles of the canonical CTCF isoform. Here, we explore the functions of an alternatively spliced human CTCF isoform in which exons 3 and 4 are skipped, producing a shorter isoform (CTCF-s). Functionally, we find that CTCF-s competes with the genome binding of canonical CTCF and binds a similar DNA sequence. CTCF-s binding disrupts CTCF/cohesin binding, alters CTCF-mediated chromatin looping and promotes the activation of IFI6 that leads to apoptosis. This effect is caused by an abnormal long-range interaction at the IFI6 enhancer and promoter. Taken together, this study reveals a non-canonical function for CTCF-s that antagonizes the genomic binding of canonical CTCF and cohesin, and that modulates chromatin looping and causes apoptosis by stimulating IFI6 expression.

Date: 2019
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DOI: 10.1038/s41467-019-08949-w

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