Transient gene melting governs the timing of oligodendrocyte maturation.

Cellular maturation is a crucial step for tissue formation and function, distinct from the initial steps of differentiation and cell fate specification. In the central nervous system, failure of oligodendrocyte maturation is linked to diseases such as multiple sclerosis. Here, we report a transcriptional mechanism that governs the timing of oligodendrocyte maturation. After progenitor cells differentiate into immature oligodendrocytes, the transcription factor SOX6 redistributes from super-enhancers to cluster across specific gene bodies. These sites exhibit extensive chromatin decondensation and transcription, which abruptly turn off upon maturation. Suppression of SOX6 deactivates these immaturity loci, accelerating the transition to mature, myelinating oligodendrocytes. Notably, cells harboring this immature SOX6 gene signature are enriched in multiple sclerosis patient brains and antisense oligonucleotide-mediated Sox6 knockdown drives oligodendrocyte maturation in mice. Our findings establish SOX6 as a key regulator of oligodendrocyte maturation and highlight its potential as a therapeutic target to promote myelination in disease.