美国Wistar研究所Alessandro Gardini团队发现，整合子的增强子模块控制细胞身份和早期神经命运决定。这一研究成果于2024年11月26日在线发表在国际学术期刊《自然—细胞生物学》上。

研究人员描述了整合子的一个增强子模块，该模块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，指导细胞命运的决定。整合子INTS10亚单位的耗竭扰乱了神经特性，并将细胞推向间充质身份。

神经增强子的启动依赖于整合子的增强子模块，该模块在细胞退出多能性时稳定SOX2在染色质上的结合。研究人员提出，整合子是增强子与启动子之间的功能性桥梁，是早期发育的主要驱动因子，这为日益增多的神经发育综合症提供了新的见解。

研究人员表示，谱系特异性转录因子通过激活选择性的顺式调控增强子和近端启动子，作为发育过程的主控者发挥作用。转录因子直接结合DNA，最终驱动特定环境下基础转录机制的招募，这些机制包括RNA聚合酶II（RNAPII）和一系列与聚合酶相关的多蛋白复合物，其中包括特有于后生动物的整合子复合物。整合子主要被认为调节RNAPII的过程性，并监控编码基因的RNA完整性。

附：英文原文

Title: The enhancer module of Integrator controls cell identity and early neural fate commitment

Author: Zhang, Yingjie, Hill, Connor M., Leach, Kelsey A., Grillini, Luca, Deliard, Sandra, Offley, Sarah R., Gatto, Martina, Picone, Francis, Zucco, Avery, Gardini, Alessandro

Issue&Volume: 2024-11-26

Abstract: 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.

DOI: 10.1038/s41556-024-01556-y

Source: https://www.nature.com/articles/s41556-024-01556-y