Highly discriminative globin gene activation by the noncanonical BAF chromatin remodeling complex

The regulation of the switch from fetal (HBG) to adult (HBB and HBD) β-globin gene expression has served as a paradigm for clinically relevant developmental transcriptional control. Mechanistic studies of this switch have predominantly focused on HBG repressors, with comparatively little attention paid to potential HBG activators. We found that in adult-type HUDEP2 erythroid cells, the ATP-dependent chromatin remodeler Brahma Related Gene 1 (BRG1) preferentially activates the HBG genes as well as the minor adult HBD gene. BRG1 is a core catalytic subunit of 3 BRG1/BRM-associated factor (BAF) complexes, canonical BAF, polybromo BAF, and noncanonical BAF (ncBAF) that regulate chromatin accessibility in distinct gene- and cell-type contexts. To dissect the specific BAF complex configuration mediating selective activation of HBG and HBD in erythroid cells, we performed CRISPR-mediated targeting of individual subunits and pinpointed the regulatory activity to the ncBAF complex. Loss of the ncBAF complex subunits BRD9 and BAF60A preferentially decreased HBG and HBD transcription while accelerating terminal erythroid differentiation and hemoglobinization. Acute pharmacological depletion of BRD9 in HUDEP2 and primary erythroid cells selectively reduced transcription of HBD and HBG, suggesting direct effects at these genes. Collectively, our unexpected findings demonstrate that the BAF complex, through distinct subcomplex configurations, can regulate selective gene expression within a multigene cluster. This expands the traditional view of BAF as a general coactivator, highlights its role in gene-specific regulation, and identifies a potential target for therapeutic manipulation of β-like globin genes in erythroid cell disorders.