BRD9 at the crossroads of splicing, chromatin remodeling, and hematopoiesis.

Abstract

BAF complexes are ATP-dependent chromatin remodelers that govern gene expression and cellular identity. The non-canonical BAF (ncBAF) complex, with BRD9 as its signature component, orchestrates chromatin remodeling essential for balanced hematopoiesis. BRD9 loss disrupts enhancer-promoter interactions and CTCF-mediated chromatin architecture, causing myeloid skewing, impaired lymphoid differentiation, and diminished hematopoietic stem cell (HSC) fitness-phenotypes recapitulating physiological aging. This mechanism underlies aging-related pathologies such as myelodysplastic syndromes (MDS), in which spliceosomal mutations in SF3B1 trigger aberrant BRD9 splicing and destabilize its mRNA. Remarkably, BRD9 exhibits context-dependent functions: its depletion consistently promotes differentiation and apoptosis in myeloid leukemias, contrasting its differential roles in myeloid differentiation in adult versus fetal hematopoiesis. Thus, BRD9 mechanistically links spliceosomal dysfunction to chromatin dysregulation, bridging aging-associated disease and malignant transformation through context-dependent roles. Among the diverse assemblies of BAF family, these findings position the BRD9-ncBAF axis as both a critical determinant of hematopoietic fate decisions and a promising therapeutic target in hematologic malignancies.