CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, 510530, Guangzhou, China.
Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China.
Nat Commun. 2019 Apr 4;10(1):1535. doi: 10.1038/s41467-019-08949-w.
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.
CTCF 在基因调控、染色质隔离、印迹、X 染色体失活和组织哺乳动物基因组的高级染色质结构中发挥关键作用。以前的研究主要集中在典型的 CTCF 同工型的作用上。在这里，我们探索了一种人 CTCF 同工型的功能，其中外显子 3 和 4 被跳过，产生一个较短的同工型（CTCF-s）。功能上，我们发现 CTCF-s 与典型的 CTCF 的基因组结合竞争，并结合相似的 DNA 序列。CTCF-s 结合破坏 CTCF/黏合蛋白结合，改变 CTCF 介导的染色质环，并促进 IFI6 的激活，导致细胞凋亡。这种效应是由 IFI6 增强子和启动子的异常长距离相互作用引起的。总之，这项研究揭示了 CTCF-s 的一种非典型功能，它拮抗典型的 CTCF 和黏合蛋白的基因组结合，并通过刺激 IFI6 表达来调节染色质环和导致细胞凋亡。
