BRD9-containing non-canonical BAF chromatin remodeling complex acts as a barrier to somatic cell reprogramming (ATAC-Seq)

Epigenetic reprogramming requires extensive remodeling of chromatin landscapes to silence gene expression programs which sustain cell identity. ATP-dependent chromatin-remodeling complexes are important regulators of chromatin structure and gene expression; however, the role of Bromodomain containing protein 9 (BRD9) and the associated ncBAF (non-canonical BRG1-associated factors) complex in somatic cell reprogramming remains unknown. Here, we show that inhibition and acute degradation of BRD9 increases the efficiency by which induced pluripotent stem cells (iPSCs) can be generated from human fibroblasts. Genetic suppression of BRD9 as well as ncBAF complex subunit GLTSCR1, but not the closely related BRD7, phenocopied this effect. CRISRP/Cas9-mediated knockout of BRD9 demonstrated that it is dispensable for establishment and maintenance of human pluripotency. Mechanistically, BRD9 inhibition facilitates reprogramming by downregulating somatic cell type-specific genes and decreasing chromatin accessibility at somatic enhancers. Collectively, these results establish BRD9 as an important safeguarding factor for somatic cell identity whose inhibition lowers barriers to reprogramming. Overall design: Examination of transposase accessible chromatin in fibroblast cells upon BRD9 inhibition or OSKM expression. Three biological replicates from each treatment were prepared. Fibroblast cells were treated with I-BRD9, dBRD9 or DMSO (control) for 5 days and cells were reprogrammed for 6 days with DMSO treatment.