Abstract: The circadian clock coordinates daily rhythmicity in cell-type specific functions. Recent studies have shown that the circadian clock can even guide changes in cellular state and fate specifications. Here, we resolve circadian patterns in the oligodendrocyte progenitor cell (OPC) transcriptome. This rhythmic expression of cell type specific gene sets establish circadian phases which are permissive to oligodendrocyte differentiation. Aligning promyelinating therapy to this specific circadian phase in vivo enhances myelination response. Disruption of the genetic clock via BMAL1 manipulation alters normal oligodendrocyte differentiation dynamics, coinciding with changes in Sox10 expression. Using CUT&RUN and HiChIP, we identified and functionally annotated BMAL1 binding sites, including an OPC-specific regulatory element that controls Sox10 expression. Collectively, these findings uncover novel mechanisms by which the circadian clock governs oligodendrocyte differentiation and highlight potential circadian-based approaches for remyelination therapy.
