Small-molecule-induced epigenetic rejuvenation overcomes myelinogenic barriers and stimulates myelin repair [RNA-seq]

Failure of oligodendrocytes to remyelinate underlies diseases such as multiple sclerosis (MS). We found that epigenetic silencing prevents oligodendrocytes from producing myelin sheaths in demyelinating MS lesions. Here, we developed a transgenic reporter system to identify a small-molecule epigenetic modulator that stimulates oligodendrocyte maturation and myelin ensheathment in vitro. This compound promoted remyelination in animal models of MS and myelination of regenerated axons and increased myelin sheath lengths in human iPSC-derived organoids. Multi-omics analyses revealed that the compound induced an enhancer/super-enhancer landscape that upregulates crucial myelinogenesis-associated pathways, including RRAS2-AKT signaling, driving actin depolymerization necessary for myelin ensheathment. Strikingly, the compound also induced phase-separated nuclear condensates of SREBP1/2, which concentrate transcriptional co-activators to drive lipid and cholesterol biosynthesis. Silencing expression of a potential target of the small molecule, HDAC3, facilitated robust myelination and remyelination. Our findings suggest that small-molecule-modulated epigenome rejuvenation relieves epigenetic silencing barriers and promotes myelin repair.少突胶质细胞无法完成髓鞘再生，是多发性硬化（multiple sclerosis, MS）等疾病的核心病理基础。我们研究发现，表观遗传沉默会阻断脱髓鞘MS病灶内少突胶质细胞生成髓鞘的过程。本研究开发了一种转基因报告系统，用于筛选可在体外促进少突胶质细胞成熟与髓鞘包裹的小分子表观遗传调节剂。该化合物可在MS动物模型中促进髓鞘再生，同时可促进再生轴突的髓鞘化，并提升人类诱导多能干细胞（induced pluripotent stem cell, iPSC）衍生类器官的髓鞘长度。多组学分析显示，该化合物重塑了增强子/超级增强子调控图谱，上调了一系列与髓鞘生成密切相关的关键通路，其中包括RRAS2-AKT信号通路，该通路可驱动髓鞘包裹过程必需的肌动蛋白解聚反应。值得注意的是，该化合物还可诱导固醇调节元件结合蛋白1/2（SREBP1/2）形成相分离核凝集体，通过聚集转录共激活因子来促进脂质与胆固醇的生物合成。沉默该小分子的潜在靶点组蛋白脱乙酰酶3（HDAC3）的表达，可显著增强髓鞘生成与髓鞘再生能力。本研究结果表明，经小分子调控的表观基因组复壮可解除表观遗传沉默屏障，进而有效促进髓鞘修复。