In-depth functional analysis of BRD9 in fetal hematopoiesis reveals context-dependent roles

The hierarchical organization of hematopoietic stem cells (HSCs) governing adult hematopoiesis has been extensively investigated. However, the dynamic epigenomic transition from fetal to adult hematopoiesis remains incompletely understood, particularly regarding the involvement of epigenetic factors. In this study, we investigate the roles of BRD9, an essential component of the non-canonical BAF (ncBAF) complex known to govern the fate of adult HSCs, in fetal hematopoiesis. Consistent with observations in adult hematopoiesis, BRD9 loss impairs fetal HSC stemness and disturbs erythroid maturation. Intriguingly, the impact on myeloid lineage was discrepant: BRD9 loss inhibited and promoted myeloid differentiation in fetal and adult models, respectively. Through comprehensive transcriptomic and epigenomic analysis, we elucidate the differential roles of BRD9 in a context- and lineage-dependent manner. Our data uncover how BRD9/ncBAF complex modulates transcription in a stage-specific manner, providing deeper insights into the epigenetic regulation underlying the transition from fetal to adult hematopoiesis.