Brg1 defect causes aberrent nucleosome landscape and affects totipotency & pluripotency transcriptional factors binding during embryogenesis [MNase-Seq]

Mammalian embryogenesis involves intricate epigenetic reprogramming and chromatin remodeling. In this study, we investigated the role of Brg1, a catalytic ATPase subunit of the SWI/SNF complex, in early embryonic development and mouse embryonic stem cell (mESC) pluripotency. By generating Smarca4 flox/flox Gdf9-Cre female mice to knockout Brg1 in MII oocytes and using CRISPR-Cas9 to knockout Brg1 in mESCs, we found that Brg1 deficiency led to multiple defects. In mouse embryos, maternal knockout of Brg1 caused reduced blastocyst formation, delayed development, elevated nucleosome occupancy at gene promoters, and dysregulation of zygotic genome activation (ZGA) genes, potentially due to disrupted binding of totipotency-related transcription factors (TFs). In mESCs, Brg1 knockout resulted in abnormal clone morphology, decreased pluripotency marker expression, and reduced cell proliferation. Brg1 affected pluripotency mainly by influencing the binding of pluripotency-related TFs such as Oct4 through enhancer accessibility. We identified those TFs as totipotency/pluripotency Brg1-dependent TFs. Overall, this study demonstrates the crucial role of Brg1 in ZGA and mESC identity maintenance in affecting specific TF binding on proximal and distal regulatory elements.