Transient gene melting governs the timing of oligodendrocyte maturation [miRNA-seq]. Transient gene melting governs the timing of oligodendrocyte maturation [miRNA-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. Overall design: Small RNA transcriptional profiling of mouse pluripotent stem cell-derived oligodendrocyte progenitor cells (OPCs) and oligodendrocytes (OL) as in vivo isolated OPCs and OLs.

细胞成熟（cellular maturation）是组织形成与功能行使的核心环节，其与分化及细胞命运特化的初始阶段截然不同。在中枢神经系统中，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。本研究揭示了调控少突胶质细胞成熟时序的转录机制。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）重新分布，并聚集于特定基因体区域。这些位点呈现广泛的染色质解聚与转录活性，并在细胞成熟后被快速沉默。抑制SOX6可使这些未成熟基因位点失活，加速细胞向成熟、具备髓鞘形成能力的少突胶质细胞转化。值得注意的是，携带此类未成熟SOX6基因特征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基因敲低可促进小鼠体内少突胶质细胞提前成熟。本研究证实SOX6是调控少突胶质细胞成熟的关键调控因子，并凸显其作为疾病状态下促进髓鞘形成的治疗靶点的潜在价值。整体实验设计：对小鼠多能干细胞诱导分化得到的少突胶质细胞祖细胞（oligodendrocyte progenitor cells, OPCs）与少突胶质细胞（oligodendrocytes, OLs），以及体内分离的OPCs与OLs进行小RNA转录谱分析。