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在基因调节，染色质绝缘，印迹，X染色体失活以及组织哺乳动物基因组的高级染色质结构中起关键作用。先前的研究主要集中在规范CTCF同工型的作用上。在这里，我们探讨了选择性剪接的人类CTCF同工型的功能，其中外显子3和4被跳过，产生了较短的同工型（CTCF-s）。在功能上，我们发现CTCF-s与规范CTCF的基因组结合竞争，并结合相似的DNA序列。CTCF-s的结合破坏了CTCF /黏附素的结合，改变了CTCF介导的染色质环化并促进了导致细胞凋亡的IFI6的激活。此效果是由IFI6增强子和启动子之间异常的远程相互作用引起的。在一起