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选定的顺式调节增强子和近端启动子，作为发育过程的主协调器发挥作用。转录因子的直接 DNA 结合最终驱动基础转录机制的环境特异性募集，该机制包括 RNA 聚合酶 II （RNAPII） 和许多聚合酶相关的多蛋白复合物，包括后生动物特异性 Integrator 复合物。Integrator 主要以调节 RNAPII 持续合成能力并监测编码基因之间的 RNA 完整性而闻名。在这里，我们描述了 Integrator 的增强子模块，它通过促进神经增强子的表观遗传变化和转录因子结合来指导细胞命运规范。Integrator 的 INTS10 亚基的耗竭会破坏神经特征并使细胞脱轨至间充质身份。神经增强子的调试依赖于 Integrator 的增强子模块，该模块在脱离多能性时稳定染色质处的 SOX2 结合。我们提出 Integrator 是增强子和启动子之间的功能桥梁，也是早期发展的主要驱动力，为不断增长的神经发育综合征家族提供了新的见解。