Abstract：
Master transcription factors such as TP63 establish super-enhancers (SEs) to drive core transcriptional networks in cancer cells, yet the spatiotemporal regulation of SEs within the nucleus remains unknown. The nuclear pore complex (NPC) may tether SEs to the nuclear pore where RNA export rates are maximal. Here, we report that NUP153, a component of the NPC, anchors SEs to the NPC and enhances TP63 expression by maximizing mRNA export. This anchoring is mediated through protein-protein interaction between the intrinsically disordered regions (IDRs) of NUP153 and the coactivator BRD4. Silencing of NUP153 excludes SEs from the nuclear periphery, decreases TP63 expression, impairs cellular growth, and induces epidermal differentiation of squamous cell carcinoma. Overall, this work reveals the critical roles of NUP153 IDRs in the regulation of SE localization, thus providing insights into a new layer of gene regulation at the epigenomic and spatial level.
摘要：
TP63等主要转录因子建立超级增强子（SE）来驱动癌细胞中的核心转录网络，然而，核内SEs的时空调控仍然未知。核孔复合物（NPC）可以将SE束缚到RNA输出速率最大的核孔。这里,我们报告NUP153，NPC的一个组成部分，将SE锚定到NPC并通过最大化mRNA输出来增强TP63表达。这种锚定是通过NUP153的内在无序区域（IDR）和共激活子BRD4之间的蛋白质-蛋白质相互作用介导的。NUP153的沉默将SEs排除在核外围，降低TP63表达，损害细胞生长，并诱导鳞状细胞癌的表皮分化。总的来说,这项工作揭示了NUP153IDRs在SE定位调控中的关键作用，从而在表观基因组和空间水平上提供了对新的基因调控层的见解。
