biostudies-literatureWang JNational Multiple Sclerosis SocietyNational Natural Science Foundation of Chinae202310143https://www.ebi.ac.uk/biostudies/studies/S-EPMC11040499biostudies-literatureUnknown223(7)Chromatin-remodeling protein BRG1/SMARCA4 is pivotal for establishing oligodendrocyte (OL) lineage identity. However, its functions for oligodendrocyte-precursor cell (OPC) differentiation within the postnatal brain and during remyelination remain elusive. Here, we demonstrate that Brg1 loss profoundly impairs OPC differentiation in the brain with a comparatively lesser effect in the spinal cord. Moreover, BRG1 is critical for OPC remyelination after injury. Integrative transcriptomic/genomic profiling reveals that BRG1 exhibits a dual role by promoting OPC differentiation networks while repressing OL-inhibitory cues and proneuronal programs. Furthermore, we find that BRG1 interacts with EED/PRC2 polycomb-repressive-complexes to enhance H3K27me3-mediated repression at gene loci associated The Journal of cell biologyBRG1 programs PRC2-complex repression and controls oligodendrocyte differentiation and remyelination.PMC11040499RG2110No. 82104181Weng QLiu XXin MYang LDu YNicholson ELu QRWang JfalseBRG1 programs PRC2-complex repression and controls oligodendrocyte differentiation and remyelination.Chromatin-remodeling protein BRG1/SMARCA4 is pivotal for establishing oligodendrocyte (OL) lineage identity. However, its functions for oligodendrocyte-precursor cell (OPC) differentiation within the postnatal brain and during remyelination remain elusive. Here, we demonstrate that Brg1 loss profoundly impairs OPC differentiation in the brain with a comparatively lesser effect in the spinal cord. Moreover, BRG1 is critical for OPC remyelination after injury. Integrative transcriptomic/genomic profiling reveals that BRG1 exhibits a dual role by promoting OPC differentiation networks while repressing OL-inhibitory cues and proneuronal programs. Furthermore, we find that BRG1 interacts with EED/PRC2 polycomb-repressive-complexes to enhance H3K27me3-mediated repression at gene loci associated 2024-01-01T00:00:00Z2024 Jul2026-07-15T04:58:22.028Z2025-04-04T02:21:05.86ZS-EPMC110404993865211810.1083/jcb.202310143