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. Profile lncRNA dynamics during oligodendrocyte differentiation and maturation