The lncRNA genomic landscape of oligodendrocytes reveals myelination control by a lncOL1/Suz12 complex in the CNS [RNASeq_DH]

Long noncoding RNAs (lncRNAs) are emerging as important regulators of cellular functions, but their roles in myelination in the CNS remain undefined. Through de novo transcriptome reconstruction at multiple stages, we establish dynamic expression profiles of lncRNAs during oligodendrocyte lineage progression and uncover a cohort of oligodendrocyte-enriched lncRNAs. Co-expression network analysis reveals a cohort of lncRNAs is linked to protein-coding genes associated with oligodendrocyte maturation. We identify a conserved chromatin-associated oligodendrocyte-restricted lncRNA, lncOL1. Overexpression of lncOL1 promotes oligodendrocyte differentiation in the developing brain, whereas genetic inactivation of lncOL1 causes defects in myelination and remyelination in the CNS. We further show that lncOL1 interacts with Suz12, a component of polycomb repressive complex 2, to promote oligodendrocyte differentiation in part through Suz12-mediated silencing of a differentiation inhibitory network that antagonizes OL maturation. Together, our findings demonstrate lncRNAs as a key layer of the genetic circuitry that controls CNS myelination and myelin repair. Overall design: Profile lncRNA dynamics during oligodendrocyte differentiation and maturation

长链非编码RNA（long noncoding RNAs，lncRNAs）作为细胞功能的重要调控因子正日益受到关注，但其在中枢神经系统（central nervous system，CNS）髓鞘形成（myelination）中的作用仍未明确。本研究通过多阶段从头转录组重构，构建了少突胶质细胞（oligodendrocyte）谱系发育进程中lncRNAs的动态表达谱，并鉴定出一组富集于少突胶质细胞的lncRNAs。共表达网络分析显示，部分lncRNAs与少突胶质细胞成熟相关的蛋白编码基因存在密切关联。本研究鉴定出一种保守的、结合染色质的少突胶质细胞特异性lncRNA，命名为lncOL1。在发育中的大脑中过表达lncOL1可促进少突胶质细胞分化，而通过遗传学手段失活lncOL1则会导致中枢神经系统髓鞘形成及髓鞘再生（remyelination）缺陷。进一步研究发现，lncOL1可与多梳抑制复合体2（polycomb repressive complex 2）的组分Suz12相互作用，通过Suz12介导的沉默拮抗少突胶质细胞成熟的分化抑制网络，从而部分促进少突胶质细胞分化。综上，本研究证实lncRNAs是调控中枢神经系统髓鞘形成与髓鞘修复的遗传调控环路中的关键层级。整体实验设计：解析少突胶质细胞分化与成熟过程中lncRNAs的动态表达特征。