Zhang Yingjie, Hill Connor M, Leach Kelsey A, Grillini Luca, Deliard Sandra, Offley Sarah R, Gatto Martina, Picone Francis, Zucco Avery, Gardini Alessandro
The Wistar Institute, Philadelphia, PA, USA.
Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nat Cell Biol. 2025 Jan;27(1):103-117. doi: 10.1038/s41556-024-01556-y. Epub 2024 Nov 26.
Lineage-specific transcription factors operate as master orchestrators of developmental processes by activating select cis-regulatory enhancers and proximal promoters. Direct DNA binding of transcription factors ultimately drives context-specific recruitment of the basal transcriptional machinery that comprises RNA polymerase II (RNAPII) and a host of polymerase-associated multiprotein complexes, including the metazoan-specific Integrator complex. Integrator is primarily known to modulate RNAPII processivity and to surveil RNA integrity across coding genes. Here we describe an enhancer module of Integrator that directs cell fate specification by promoting epigenetic changes and transcription factor binding at neural enhancers. Depletion of Integrator's INTS10 subunit upends neural traits and derails cells towards mesenchymal identity. Commissioning of neural enhancers relies on Integrator's enhancer module, which stabilizes SOX2 binding at chromatin upon exit from pluripotency. We propose that Integrator is a functional bridge between enhancers and promoters and a main driver of early development, providing new insight into a growing family of neurodevelopmental syndromes.
谱系特异性转录因子通过激活特定的顺式调控增强子和近端启动子，作为发育过程的主要协调者发挥作用。转录因子与DNA的直接结合最终驱动了基础转录机制的上下文特异性募集，该机制由RNA聚合酶II（RNAPII）和许多与聚合酶相关的多蛋白复合物组成，包括后生动物特有的整合子复合物。整合子主要已知可调节RNAPII的持续性，并监测编码基因的RNA完整性。在这里，我们描述了整合子的一个增强子模块，它通过促进表观遗传变化和转录因子在神经增强子上的结合来指导细胞命运特化。整合子的INTS10亚基的缺失颠覆了神经特征，并使细胞转向间充质特性。神经增强子的启用依赖于整合子的增强子模块，该模块在多能性退出时稳定SOX2在染色质上的结合。我们提出，整合子是增强子和启动子之间的功能桥梁，也是早期发育的主要驱动因素，为越来越多的神经发育综合征家族提供了新的见解。
