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Olig2 is a basic helix–loop–helix transcription factor that plays a critical role in the central nervous system. It directs the specification of motor neurons and oligodendrocyte precursor cells (OPCs) from neural progenitors and the subsequent maturation of OPCs into myelin-forming oligodendrocytes (OLs). It is also required for the development of astrocytes. Despite a decade-long search, enhancers that regulate the expression of  Olig2  remain elusive. We have recently developed an innovative method that maps promoter-distal enhancers to genes in a principled manner. Here, we applied it to  Olig2  in the context of OL lineage cells, uncovering an OL enhancer for it (termed Olig2-E1). Silencing Olig2-E1 by CRISPRi epigenome editing significantly downregulated  Olig2  expression. Luciferase assay and ATAC-seq and ChIP-seq data show that Olig2-E1 is an OL-specific enhancer that is conserved across human, mouse and rat. Hi-C data reveal that Olig2-E1 physically interacts with  OLIG2  and suggest that this interaction is specific to OL lineage cells. In sum, Olig2-E1 is an evolutionarily conserved OL-specific enhancer that drives the expression of  Olig2 .

Identifying an oligodendrocyte enhancer that regulates Olig2 expression