SRA

Cell fate specification occurs via coordinated transcriptional changes in pluripotent cells, resulting in progressive commitment towards distinct lineages. Lineage-specific transcription factors (TFs), through their intrinsic DNA-binding ability, operate as master orchestrators of early and late developmental processes by turning on select cis-regulatory enhancers and proximal promoter elements. TF binding ultimately drives 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. Here we show that a set of Integrator subunits (enhancer module) plays a direct role in cell fate specification by promoting epigenetic changes and TF binding at enhancer elements that drive neurogenesis and maintain neuronal cell identity. Depletion of a single Integrator subunit (INTS10) results in loss of molecular and morphological neuronal features, while diverting progenitor cells towards mesenchymal identity. Commissioning of developmental enhancers rely on Integrator's enhancer module, which stabilizes SOX2 binding at chromatin upon exit from pluripotency. Integrator therefore operates as a functional bridge between enhancers and target promoters and is a driver of early developmental processes, providing new insight into a growing family of neurodevelopmental syndromes. Overall design: INTS10/11/13, RNAPII, H3K27ac, H3K4me1 was ChIPed in WT and INTS10heterzyogote iPSCs/NPCs and WT Neurons. H3K27me3 was ChIPed in WT and INTS10heterzyogote NPCs. INTS10/11/13 and RNAPII were ChIP in WT SHSY5Y cells.