Dysregulation of transcription networks regulating oligodendrogenesis in age-related decline in CNS remyelination

In demyelinating diseases like multiple sclerosis (MS), efficient remyelination is critical for functional recovery. Remyelination efficiency declines with age, and is linked to progressive disability. The gene regulatory network underlying remyelination, and how it is altered with aging, remains unclear. Here we present a comparative single-nucleus RNA and ATAC sequencing analysis of remyelination in young and aged mice. We identified gene modules dynamically expressed throughout oligodendrocyte differentiation, revealing age-dependent changes in key processes related to myelination. Multi-omic analysis allowed us to map the regulatory network driving efficient remyelination within oligodendrocyte lineage cells in young mice. We highlight key transcription factors in the network dysregulated with age, and we describe similar dysregulations in MS lesions. Modifying the expression of these transcription factors in primary oligodendrocyte progenitor cells impacts differentiation. These findings provide a foundational understanding of this regenerative process in the context of aging and in chronic demyelinating diseases.