2026年10月28日，美国康奈尔大学Cem Meydan等科学家在《自然》发表研究，揭示SWI/SNF复合物通过CTCF和黏连蛋白塑造3D染色质架构。

BAF（也称为哺乳动物SWI/SNF）染色质重塑复合物是核小体定位和转录因子结合的重要调控因子。编码BAF复合物组分的基因中的功能缺失（LOF）突变是多种癌症中最常见的突变之一。然而，解释其广泛破坏的统一机制仍不清楚。在此，研究人员通过药理学抑制和ARID1A缺失，在多种哺乳动物细胞类型和组织中破坏BAF功能，并观察到一种保守的染色质反应：CTCF结合位点的可及性增加。仅ARID1A功能缺失就足以驱动这些变化，表明经典BAF（cBAF）破坏是CTCF占据增加的关键驱动因素。基因组分析显示CTCF和SMC3占据增加，揭示了cBAF与CTCF–黏连蛋白复合物之间的拮抗关系。此外，cBAF缺失重塑了3D基因组组织，导致拓扑关联结构域边界增强，并将大结构域细分为更小的绝缘结构。长距离增强子–启动子环被锚定在CTCF富集位点的更短、靠近启动子的环所取代。为确定cBAF缺失后CTCF功能如何被启用，研究人员分析了与CTCF相互作用的辅因子，发现CTCF直接结合完全组装的PBAF。cBAF耗竭后，PBAF被招募到CTCF占据增加的位点，表明SWI/SNF亚复合物之间存在拮抗性转换。在体内，原代小鼠细胞中条件性Arid1a缺失导致一个高度增殖群体的扩增，其特征是CTCF位点可及性升高。这一表型通过Ctcf或Pbrm1缺失被完全逆转，表明cBAF与CTCF和PBAF的活性具有相反作用。

附：英文原文

Title: SWI/SNF complexes shape 3D chromatin architecture through CTCF and cohesin

Author: Debek, Sonia, Meydan, Cem, Chin, Christopher R., Yu, Jiali, Durmaz, Ceyda, Tsialta, Ioanna, Pelzer, Benedikt, Maurer, Constance, Ou, Arnold, Laguillo-Diego, Alejandra, Scourzic, Laurianne, Tumuluru, Sravya, Teater, Matt, Wu, Rui, Darsow, Brian, Rivas, Martin A., Marin-Rubio, Jose Luis, Stadtfeld, Matthias, Apostolou, Effie, Mason, Christopher E., Elenitoba-Johnson, Kojo S. J., Risca, Viviana I., Melnick, Ari, Barisic, Darko

Issue&Volume: 2026-10-28

Abstract: The BAF (also known as mammalian SWI/SNF) chromatin remodelling complexes are essential regulators of nucleosome positioning and transcription factor binding1,2. Loss-of-function (LOF) mutations in genes encoding components of the BAF complexes are among the most frequent across cancer types3. However, a unifying mechanism that explains their widespread disruption remains unclear. Here we disrupted BAF function through pharmacological inhibition and ARID1A deletion across various mammalian cell types and tissues and observed a conserved chromatin response: increased accessibility at CTCF-binding sites. ARID1A LOF alone was sufficient to drive these changes, which demonstrates that canonical BAF (cBAF) disruption is the key driver of CTCF gain. Genomic profiling showed increased CTCF and SMC3 occupancy, which reveals an antagonistic relationship between cBAF and CTCF–cohesin complexes. Furthermore, cBAF loss restructured 3D genome organization, which led to a strengthening of topologically associating domain boundaries and subdivision of large domains into smaller insulated structures. Long-range enhancer–promoter loops were replaced by shorter, promoter-proximal loops anchored at CTCF-enriched sites. To determine how CTCF function is enabled following cBAF loss, we profiled CTCF-interacting cofactors and found that CTCF binds directly to fully assembled PBAF. After cBAF depletion, PBAF was recruited to sites of increased CTCF occupancy, which demonstrates that there is an antagonistic switch between SWI/SNF subcomplexes. In vivo, conditional Arid1a deletion in primary mouse cells resulted in the expansion of a highly proliferative population marked by elevated accessibility at CTCF sites. This phenotype was fully reversed by either Ctcf or Pbrm1 deletion, which establishes that cBAF and the activity of CTCF and PBAF have contrasting roles.

DOI: 10.1038/s41586-026-11197-w

Source:https://www.nature.com/articles/s41586-026-11197-w