The lncRNA MYRACL regulates human oligodendrocyte maturation and myelination

Recent studies have described disease-associated expression patterns of long non-coding RNAs (lncRNAs) associated with neurodevelopment and neurodegeneration, highlighting their potential as regulators of function and therefore potential therapeutic targets. Oligodendrocyte (OL) dysfunction drives central nervous system myelin disruption in neurological disorders, but the mechanisms underlying impaired myelin patterns are still poorly understood. In this study, we uncover a role for the lncRNA MYRACL (myelination regulating oligodendrocyte-associated lncRNA) as a regulator of functional maturation and OL myelination. Analysis of RNA-sequencing data performed in human postmortem brain tissue revealed MYRACL to be among the top enriched genes expressed in the OL population compared to the OL precursor cell cluster. We validated this finding in an embryonic stem cell-derived oligodendroglia cell culture model. Analysis of evolutionary conservation and protein coding potential showed that MYRACL is non-coding and may exhibit conserved regions across mammalian species. Further co-expression analysis of lncRNAs-mRNAs suggested that expression of MYRACL positively correlates with genes known to be involved in driving oligodendroglia differentiation. GapmeR-mediated knockdown of nuclear MYRACL disrupted OL maturation in vitro, while lentivirus-mediated overexpression promoted OL differentiation with enhancement of myelin formation in vitro. Our findings highlight MYRACL as a novel regulatory mechanism in human OL maturation and myelination. By providing a human, translationally relevant platform, this work advances our ability to model human myelination in vitro and paves the way for precision medicine approaches targeting lncRNA-mediated dysregulation in neurodevelopmental and neurodegenerative diseases.