BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state [scRNA-Seq]

Chromatin remodeling caused by SWI/SNF (BAF) complexes is essential for regulating cell fates. Of these, BRD9, an essential component of the non-canonical BAF (ncBAF) complex, is post-transcriptionally decayed in multiple types of cancer, especially in myelodysplastic syndrome (MDS). However, how BRD9 loss or ncBAF disruption alters the HSCs' integrity remains unknown. Here, we identify that Brd9 loss enhances chromatin accessibility, promoting myeloid-lineage skewing at the expense of B cell development in vivo, followed by MDS development. Brd9 significantly colocalizes with Ctcf, whose peaks are stoichiometrically enhanced by Brd9 loss, leading to increased chromatin loops with the larger chromatin domains intact. These Ctcf-associated chromatin loops newly occur in myeloid-related genes. These data uncover the unrecognized roles of BRD9/ncBAF in the cell fate specification of HSCs via fine-tuning chromatin loops and shed light on the mechanism of ncBAF-disrupted cancer. Overall design: Four weeks after birth, the primary mice received 20 mg/kg pIpC injection every other day for a total of 3 doses. Eight weeks after pIpC injection, the primary mice were sacrificed for sample preparation.