He Danyang, Wang Jincheng, Lu Yulan, Deng Yaqi, Zhao Chuntao, Xu Lingli, Chen Yinhuai, Hu Yueh-Chiang, Zhou Wenhao, Lu Q Richard
Divisions of Experimental Hematology and Cancer Biology & Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Integrative Biology Graduate Training Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Divisions of Experimental Hematology and Cancer Biology & Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Zhejiang Province Key Laboratory of Anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, 310058 Hangzhou, China.
Neuron. 2017 Jan 18;93(2):362-378. doi: 10.1016/j.neuron.2016.11.044. Epub 2016 Dec 29.
Long noncoding RNAs (lncRNAs) are emerging as important regulators of cellular functions, but their roles in oligodendrocyte myelination remain undefined. Through de novo transcriptome reconstruction, we establish dynamic expression profiles of lncRNAs at different stages of oligodendrocyte development and uncover a cohort of stage-specific oligodendrocyte-restricted lncRNAs, including a conserved chromatin-associated lncOL1. Co-expression network analyses further define the association of distinct oligodendrocyte-expressing lncRNA clusters with protein-coding genes and predict lncRNA functions in oligodendrocyte myelination. Overexpression of lncOL1 promotes precocious oligodendrocyte differentiation in the developing brain, whereas genetic inactivation of lncOL1 causes defects in CNS myelination and remyelination following injury. Functional analyses illustrate that lncOL1 interacts with Suz12, a component of polycomb repressive complex 2, to promote oligodendrocyte maturation, in part, through Suz12-mediated repression of a differentiation inhibitory network that maintains the precursor state. Together, our findings reveal a key lncRNA epigenetic circuitry through interaction with chromatin-modifying complexes in control of CNS myelination and myelin repair.
长链非编码RNA（lncRNAs）正逐渐成为细胞功能的重要调节因子，但其在少突胶质细胞髓鞘形成中的作用仍不明确。通过从头转录组重建，我们建立了少突胶质细胞发育不同阶段lncRNAs的动态表达谱，并发现了一组阶段特异性的少突胶质细胞限制性lncRNAs，包括一个保守的染色质相关lncOL1。共表达网络分析进一步确定了不同的少突胶质细胞表达的lncRNA簇与蛋白质编码基因的关联，并预测了lncRNA在少突胶质细胞髓鞘形成中的功能。lncOL1的过表达促进发育中大脑少突胶质细胞的早熟分化，而lncOL1的基因失活会导致中枢神经系统髓鞘形成和损伤后髓鞘再生缺陷。功能分析表明，lncOL1与多梳抑制复合物2的一个组分Suz12相互作用，部分通过Suz12介导的对维持前体状态的分化抑制网络的抑制来促进少突胶质细胞成熟。总之，我们的研究结果揭示了一个关键的lncRNA表观遗传回路，其通过与染色质修饰复合物相互作用来控制中枢神经系统髓鞘形成和髓鞘修复。
