lncRNA Functional Networks in Oligodendrocytes Reveal Stage-Specific Myelination Control by an lncOL1 /Suz12 Complex in the CNS

Abstract

Summary 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.

Characterization of a long noncoding RNA Pcdh17it as a novel marker for immature premyelinating oligodendrocytes

“…It has been shown that Wave1/Wsf1 knockout in mice leads to fewer OL processes per cell and hypomyelination in the white matter (Kim et al, ). Despite the fact that no significant correlation was found between Pcdh17 and Pcdh17it expression by an earlier bioinformatics analysis (He et al, ), we discovered that they are largely co‐expressed in imOLs (Figure S5e,f; A. Fudge and H. Li unpublished observations). Taken together, the available evidence suggests that Pcdh17 might take part in the initiation of myelination by regulating f‐actin assembly while Pcdh17it might fine‐tune the level of Pcdh17 expression.…”

“…We provide evidence that Pcdh17it is specifically expressed in imOLs and is present in cytoplasm and/or nucleus (Figure ). Pcdh17it (also known as 9630013A20Rik or lncOL1 ) was reported to regulate OL differentiation through interaction with polycomb repressive complex 2 (Prc2) via Suz12 (He et al, ). The Pcdh17it gene lies inside intron 1 of the Pcdh17 gene (encoding cell–cell adhesion molecule Protocadherin 17), in the antisense direction, on mouse chromosome 14.…”

“…Here, tapping into available data, we identify an OL lineage‐specific long noncoding RNA (lncRNA; Zhang et al, ) that is down‐regulated in myelinating OLs and provide evidence that this lncRNA (named Pcdh17it ) is a specific marker for immature, premyelinating imOLs. This lncRNA has previously been named 9630013A20Rik (Zeisel et al, ), lncOL1 (He et al, ), and Pcdh17it (Marques et al, ), and we adopt the name Pcdh17it in accord with the guidelines of the HUGO Gene Nomenclature Committee (Wright, ). In addition, we show that Pcdh17it expressing cells in adult mouse brain are newly generated cells and, with the help of this new marker, we demonstrate OL generation over the lifespan in mouse forebrain.…”

Analysis of Long Noncoding RNA and mRNA Expression Profiles in IL-9-Activated Astrocytes and EAE Mice

“…Emerging evidence indicates that lncRNAs not only participate in autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriasis [25-27], but also play important roles in CNS development, homeostasis, stress responses, and plasticity [28]. Recent work points to the role of lncRNAs in oligodendrocyte precursor cell (OPC) differentiation from neural stem cells (NSCs), myelination and remyelination in the CNS [29, 30]. lncRNA (Malat1) displays anti–apoptotic and anti-inflammatory roles in microvasculature structure of the brain to reduce ischemic brain injury [31].…”

Epigenetic modifications—insight into oligodendrocyte lineage progression, regeneration, and disease

“…Histone methyltransfereases (HMT) like Ezh2 in the PRC2 complex can cause chromatin compaction by trimethylation of histone K27, which leads to a repressive state . Ezh2 has been shown to promote murine oligodendrocyte proliferation from NSCs in vitro [Sher et al ., 2008], while deletion of the murine Ezh2 in Olig1 + early progenitors led to dramatic reduction in mature oligodendrocytes and myelination in mice .…”