Transcription Factors Recruit the Cohesin Loader NIPBL to Promote Chromatin Looping and Long-range Gene Regulation

The cohesin complex is central to chromatin looping, but mechanisms by which these long-range chromatin interactions are formed and persist remain unclear. We demonstrate that interactions between a transcription factor and the cohesin loader NIPBL regulate enhancer-promoter looping and promote long-range gene regulation. Using mass-spectrometry, genome mapping, and single-molecule tracking methods, we demonstrate that NIPBL and cohesin regulate the dynamics and function of the glucocorticoid receptor (GR). Moreover, glucocorticoid treatment stabilizes NIPBL and cohesin interactions by promoting loop extrusion and chromatin looping. Patient-derived acute myeloid leukemia cells harboring cohesin mutations exhibit a reduced response to glucocorticoids (GCs), suggesting that the GR-NIPBL-cohesin interaction is defective in these patients, and they may be poor candidates for GC treatment. We examined the long-range interactions mediated by GR and how NIPBL influences these structures

黏连蛋白复合物（cohesin complex）是染色质环化的核心调控因子，但此类长距离染色质互作的构建与维持机制仍不明确。本研究证实，转录因子与黏连蛋白加载因子NIPBL之间的相互作用，可调控增强子-启动子环化并促进长距离基因调控。本研究借助质谱（mass-spectrometry）、基因组作图与单分子追踪技术，证明NIPBL与黏连蛋白可调控糖皮质激素受体（glucocorticoid receptor, GR）的动态特性与功能。此外，糖皮质激素处理可通过促进环挤出与染色质环化，稳定NIPBL与黏连蛋白的相互作用。携带黏连蛋白突变的患者来源急性髓系白血病细胞，对糖皮质激素（glucocorticoids, GCs）的响应能力减弱，这提示此类患者体内GR-NIPBL-黏连蛋白互作存在缺陷，或不适合采用GC治疗。本研究还探究了GR介导的长距离染色质互作，以及NIPBL对这类染色质结构的调控作用。