Transcriptional regulation in oligodendrocytes: Functional interaction of the transcription factor Sox10 with Myrf and interplay with Sox8

The transcription factor Sox10 is one of the key regulators of oligodendrocyte differentiation and myelination. Expression of Sox10 is induced in oligodendrocyte precursor cells (OPCs) and is maintained in the mature myelinating stage. During oligodendrocyte terminal differentiation, Sox10 induces many genes that are required for myelination and is helped in its function by the myelin regulatory factor Myrf. The present study shows that Myrf not only cooperates with Sox10 in the induction of genes that are required during oligodendrocyte terminal differentiation and myelination. Myrf also prevents Sox10 from activating genes that are crucial for early oligodendroglial development. Functional characterization of the transcriptional activity of Myrf revealed that synergistic activation requires the joint binding of Sox10 and Myrf in the oligodendrocyte-specific regulatory regions. By contrast, the absence of binding sites that allow strong binding of Myrf in the OPC-specific regulatory regions results in the inhibition of the Sox10-dependent activation. This physical interaction between Myrf and Sox10 leads to the sequestration of Sox10 from specific target genes. These data add new insights into the complex regulatory network established by Sox10 and Myrf, where Myrf is first induced by Sox10 and then in turn functions as a modulatory switch for Sox10 activity. It directs Sox10 from activating genes required at an earlier stage of oligodendroglial development to the ones required later for differentiation and myelination. In addition to the transcription factor Sox10, the other two members of the SoxE family are Sox8 and Sox9. SoxE proteins are differentially expressed during oligodendrocyte development. Compared to Sox10, Sox8 expression begins earlier in progenitors. Later, both SoxE proteins are expressed similarly throughout oligodendroglial lineage progression and maturation. According to previous evidence, the two transcription factors are thought to act in a partially redundant manner. The present study addressed functional equivalence and differences between Sox8 and Sox10. RNA-Seq data revealed an immune-related transcriptional remodeling in a Sox10-deficient oligodendrocyte cell line upon overexpression of Sox8. These data uncover a new unknown function of Sox8 in regulating immune system-related genes and provide new insights into why mutations near the SOX8 gene in humans are correlated with an increased risk of developing multiple sclerosis.