Transient gene melting governs the timing of oligodendrocyte maturation [ATAC-seq]

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. Antisense oligonucleotide-mediated Sox6 knockdown drives precocious 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. Chromatin accessibilty of pluripotent stem cell derived oligodendrocyte progenitor cells (OPCs) and oligodendrocytes (OL)

细胞成熟是组织形成与功能发挥的关键环节，其与细胞分化（cell differentiation）及细胞命运特化（cell fate specification）的初始阶段存在显著差异。在中枢神经系统（central nervous system）中，少突胶质细胞（oligodendrocyte）成熟障碍与多发性硬化（multiple sclerosis）等疾病密切相关。本研究揭示了一种调控少突胶质细胞成熟时序的转录调控机制：当祖细胞分化为未成熟少突胶质细胞后，转录因子SOX6会从超级增强子（super enhancers）处重新分布，并聚集于特定基因体（gene bodies）区域。这些区域呈现广泛的染色质解凝（chromatin decondensation）与转录活性，且会在细胞成熟时被骤然关闭。抑制SOX6的表达可使这些未成熟基因位点（immaturity loci）失活，加速细胞向成熟的、具备髓鞘形成能力的少突胶质细胞转化。值得注意的是，携带该未成熟SOX6基因特征（gene signature）的细胞在多发性硬化患者的脑组织中富集。反义寡核苷酸（antisense oligonucleotide）介导的Sox6基因敲低（knockdown）可促进小鼠体内少突胶质细胞的早熟成熟。本研究证实SOX6是调控少突胶质细胞成熟的关键调控因子，并凸显其作为促进疾病状态下髓鞘形成治疗靶点的潜在价值。多能干细胞（pluripotent stem cell）来源的少突胶质细胞祖细胞（oligodendrocyte progenitor cells, OPCs）与少突胶质细胞（oligodendrocytes, OL）的染色质可及性（chromatin accessibility）。