Establishment of oligodendrocyte identity is crucial for subsequent events of myelination in the CNS. Here, we demonstrate that activation of ATP-dependent SWI/SNF chromatin-remodeling enzyme Smarca4/Brg1 at the differentiation onset is necessary and sufficient to initiate and promote oligodendrocyte lineage progression and maturation. Genome-wide multistage studies by ChIP-seq reveal that oligodendrocyte-lineage determination factor Olig2 functions as a prepatterning factor to direct Smarca4/Brg1 to oligodendrocyte-specific enhancers. Recruitment of Smarca4/Brg1 to distinct subsets of myelination regulatory genes is developmentally regulated. Functional analyses of Smarca4/Brg1 and Olig2 co-occupancy relative to chromatin epigenetic marking uncover stage-specific cis-regulatory elements that predict sets of transcriptional regulators controlling oligodendrocyte differentiation. Together, our results demonstrate that regulation of the functional specificity and activity of a Smarca4/Brg1-dependent chromatin-remodeling complex by Olig2, coupled with transcriptionally linked chromatin modifications, is critical to precisely initiate and establish the transcriptional program that promotes oligodendrocyte differentiation and subsequent myelination of the CNS.
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