BRD9-containing non-canonical BAF chromatin remodeling complex acts as a barrier to somatic cell reprogramming (RNA-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. Examination of BRD9 inhibition's effect on gene expression profile of fibroblast cells. Three biological replicates from each condition were prepared. Fibroblast cells were treated with BI-7273, I-BRD9, dBRD9 or DMSO (control) for 5 days or fibroblast cells were transduced with lentiviral contructs to express Cas9 and gRNA targeting BRD9 or non-targeting gRNA (control). An iPSC clone was also used to understand gene expression profile of pluripotent stem cells.