SUMMARY
Pluripotent stem cells (PSCs) provide an unlimited source for generating somatic cell types. However, generating fully mature cells constitutes a bottleneck for realizing their full potential in research and medicine. Here, we report a transcriptional mechanism that governs the timing of cellular maturation in post-mitotic oligodendrocytes. During differentiation of PSCs to oligodendrocytes, the transcription factor SOX6 redistributes from nearly all super enhancers in proliferating oligodendrocyte progenitor cells to cluster across specific gene bodies in immature oligodendrocytes. These sites exhibit ‘gene melting’, a process of extensive chromatin decondensation and transcription, which abruptly turns off upon maturation. Suppression of SOX6 deactivates these immaturity loci, resulting in rapid transition to mature myelinating oligodendrocytes. Cells harboring this immature oligodendrocyte SOX6 gene signature are specifically enriched in multiple sclerosis patient brains, suggestive that failed maturation may contribute to limited myelin regeneration in disease. Collectively, our finding that maturation rate is controlled by transient transcriptional clusters may inform approaches to accelerate the generation and regeneration of mature cell types.
HIGHLIGHTS
Transcription factors (TFs) can act as gatekeepers of post-mitotic cellular maturation
In oligodendrocytes, clustering of SOX6 controls the immaturity program through transient gene melting
Suppressing SOX6 deactivates immaturity genes and unlocks oligodendrocyte maturation
SOX6 immaturity signature is enriched in oligodendrocytes in multiple sclerosis patients
Competing Interest Statement
K.C.A., T.E.M., M.S.E., and P.J.T. are listed as inventors on pending patent claims filed by Case Western Reserve University covering methods to accelerate cellular maturation. All other authors declare no competing interests related to this work.
