BRG1 establishes the neuroectodermal chromatin landscape to restrict dorsal cell fates

Cell fate decisions are achieved with gene expression changes driven by lineage-specific transcription factors (TFs). These TFs depend on chromatin remodelers including the BAF complex to activate target genes. BAF complex subunits are essential for development and frequently mutated in cancer. Thus, interrogating how BAF complexes contribute to cell fate decisions is critical for human health. We examined the requirement for the catalytic BAF subunit BRG1 in neural progenitor cell (NPC) specification from human embryonic stem cells. During the earliest stages of differentiation, BRG1 was required to establish chromatin accessibility at neuroectoderm-specific enhancers. BRG1 depletion resulted in abnormal NPC populations that differentially expressed neuroectodermal TFs, were more prone to neuronal differentiation, and precociously formed neural crest lineages. These findings demonstrate that BRG1 mediates NPC specification by ensuring proper expression of lineage-specific TFs and appropriate activation of their transcriptional programs. RNAseq, single cell RNAseq, ATAC-seq, and Cut&Tag in H1 human embryonic stem cells and H1 cell during NPC differentiation. Cells were treated with Doxycycline to induce expression of BRG1 shRNA or treated with PROTAC to degrade BRG1