Here, we show a subset of genes that should be repressed to guarantee the OPC differentiation and myelination program are suppressed by a transcriptional inhibition machinery consisting of OLIG2 and SETDB1. OLIG2 guides and reloads the H3K9me3 deposition along the genome to promote the generation of iOLs from OPCs. Disrupting OLIG2-SETDB1 complex in the early OL lineage causes hypomyelination in mice. Our findings disclose a distinct mechanism that OLIG2 composed a TF-Epigenetic complex to conduct gene inhibition, for OL cell fate determination and myelination.
