哥本哈根大学Chunaram Choudhary小组宣布他们探明了解析CTCF和黏结蛋白在基因调控中的结构和非结构功能。该研究于2025年11月18日发表于国际一流学术期刊《自然—遗传学》杂志上。

在这里，该课题组显示了单核细胞中黏结蛋白或CTCF的急性去除会导致数百个基因失调。内聚蛋白缺失主要下调CBP/p300依赖的假定增强子靶标，而CTCF缺失则上调和下调增强子靶标。除了环锚定之外，CTCF还直接调节转录，根据其在启动子上的结合位置和取向，它可以作为激活剂或抑制剂。在机制上，CTCF激活时增加DNA的可及性并促进RNA聚合酶II的募集；当抑制时，它阻止RNA聚合酶II结合而不改变染色质的可及性。启动子结合的CTCF激活了细胞增殖所必需的恒温基因。CTCF的转录激活功能——但不是它的环锚定作用——与它的脊椎动物特异性类似物CTCFL共享。这些发现调和了内聚蛋白和CTCF的结构和非结构作用，为它们在依赖增强子和不依赖增强子的转录控制中的功能提供了统一的模型。

据介绍，内聚蛋白和CTCF介导的染色质环促进增强子-启动子和启动子-启动子相互作用，但它们对全球基因调控的影响仍存在争议。

附：英文原文

Title: Disentangling the architectural and non-architectural functions of CTCF and cohesin in gene regulation

Author: Narita, Takeo, Kilic, Sinan, Higashijima, Yoshiki, Scherer, Natalie M., Pappas, Georgios, Maskey, Elina, Choudhary, Chunaram

Issue&Volume: 2025-11-18

Abstract: Cohesin- and CTCF-mediated chromatin loops facilitate enhancer–promoter and promoter–promoter interactions, but their impact on global gene regulation remains debated. Here we show that acute removal of cohesin or CTCF in mouse cells dysregulates hundreds of genes. Cohesin depletion primarily downregulates CBP/p300-dependent putative enhancer targets, whereas CTCF loss both up- and downregulates enhancer targets. Beyond loop anchoring, CTCF directly modulates transcription, acting as an activator or repressor depending on its binding position and orientation at promoters. Mechanistically, when activating, CTCF increases DNA accessibility and promotes RNA polymerase II recruitment; when repressing, it prevents RNA polymerase II binding without altering chromatin accessibility. Promoter-bound CTCF activates housekeeping genes essential for cell proliferation. CTCF’s transcriptional activation function—but not its loop anchoring role—is shared with its vertebrate-specific paralog, CTCFL. These findings reconcile architectural and non-architectural roles of cohesin and CTCF, offering a unified model for their functions in enhancer-dependent and enhancer-independent transcription control.

DOI: 10.1038/s41588-025-02404-x

Source: https://www.nature.com/articles/s41588-025-02404-x