Aboreden Nicholas G, Zhao Han, Shan Fengnian, Liu Fuhai, Zhang Haoyue, Blobel Gerd A
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
bioRxiv. 2025 Feb 8:2025.01.12.632634. doi: 10.1101/2025.01.12.632634.
NIPBL promotes chromatin loop extrusion by the cohesin complex until it stalls at convergently oriented CTCF sites, leading to the formation of structural loops. However, to what extent loop extrusion contributes to the establishment vs maintenance of -regulatory element (CRE) connectivity is poorly understood. Here, we explored the de novo establishment of chromatin folding patterns at the mitosis-to-G1-phase transition upon acute NIPBL loss. NIPBL depletion primarily impaired the formation of cohesion-mediated structural loops with NIPBL dependence being proportional to loop length. In contrast, the majority of CRE loops were established independently of loop extrusion regardless of length. However, NIPBL depletion slowed the re-formation of CRE loops with weak enhancers. Transcription of genes at NIPBL-independent loop anchors was activated normally in the absence of NIPBL. In sum, establishment of most regulatory contacts and gene transcription following mitotic exit is independent of loop extrusion.
NIPBL通过黏连蛋白复合物促进染色质环挤压，直到它在同向排列的CTCF位点处停滞，从而导致结构环的形成。然而，环挤压在多大程度上有助于调控元件（CRE）连接性的建立与维持，目前还知之甚少。在这里，我们探讨了在急性NIPBL缺失时，从有丝分裂到G1期过渡过程中染色质折叠模式的从头建立。NIPBL缺失主要损害了黏连介导的结构环的形成，NIPBL依赖性与环长度成正比。相比之下，大多数CRE环的建立与环挤压无关，无论其长度如何。然而，NIPBL缺失减缓了与弱增强子相关的CRE环的重新形成。在没有NIPBL的情况下，NIPBL非依赖性环锚定处的基因转录正常激活。总之，有丝分裂退出后大多数调控接触和基因转录的建立与环挤压无关。
