Fettweis Gregory, Wagh Kaustubh, Stavreva Diana A, Jiménez-Panizo Alba, Kim Sohyoung, Lion Michelle, Alegre-Martí Andrea, Rinaldi Lorenzo, Johnson Thomas A, Krishnamurthy Manan, Wang Li, Ball David A, Karpova Tatiana S, Upadhyaya Arpita, Vertommen Didier, Recio Juan Fernández, Estébanez-Perpiñá Eva, Dequiedt Franck, Hager Gordon L
Laboratory of Gene Expression and Cancer, GIGA-Molecular & Computational Biology, University of Liège, 4000 Liège, Belgium.
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
bioRxiv. 2025 Feb 19:2024.12.09.627537. doi: 10.1101/2024.12.09.627537.
While the cohesin complex is a key player in genome architecture, how it localizes to specific chromatin sites is not understood. Recently, we and others have proposed that direct interactions with transcription factors lead to the localization of the cohesin-loader complex (NIPBL/MAU2) within enhancers. Here, we identify two clusters of LxxLL motifs within the NIPBL sequence that regulate NIPBL dynamics, interactome, and NIPBL-dependent transcriptional programs. One of these clusters interacts with MAU2 and is necessary for the maintenance of the NIPBL-MAU2 heterodimer. The second cluster binds specifically to the ligand-binding domains of steroid receptors. For the glucocorticoid receptor (GR), we examine in detail its interaction surfaces with NIPBL and MAU2. Using AlphaFold2 and molecular docking algorithms, we uncover a GR-NIPBL-MAU2 ternary complex and describe its importance in GR-dependent gene regulation. Finally, we show that multiple transcription factors interact with NIPBL-MAU2, likely using interfaces other than those characterized for GR.
虽然黏连蛋白复合体是基因组架构中的关键因子，但其如何定位于特定染色质位点尚不清楚。最近，我们和其他研究人员提出，与转录因子的直接相互作用会导致黏连蛋白装载复合体（NIPBL/MAU2）定位于增强子内。在此，我们在NIPBL序列中鉴定出两簇LxxLL基序，它们调节NIPBL的动态变化、相互作用组以及NIPBL依赖的转录程序。其中一簇与MAU2相互作用，是维持NIPBL-MAU2异二聚体所必需的。第二簇则特异性结合类固醇受体的配体结合结构域。对于糖皮质激素受体（GR），我们详细研究了其与NIPBL和MAU2的相互作用表面。利用AlphaFold2和分子对接算法，我们发现了一种GR-NIPBL-MAU2三元复合体，并描述了其在GR依赖的基因调控中的重要性。最后，我们表明多种转录因子与NIPBL-MAU2相互作用，可能使用的是不同于GR所特有的那些界面。
