Long non-coding RNAs in nervous system function and disease

Abstract

Central nervous system (CNS) development, homeostasis, stress responses, and plasticity are all mediated by epigenetic mechanisms that modulate gene expression and promote selective deployment of functional gene networks in response to complex profiles of interoceptive and environmental signals. Thus, not surprisingly, disruptions of these epigenetic processes are implicated in the pathogenesis of a spectrum of neurological and psychiatric diseases. Epigenetic mechanisms involve chromatin remodeling by relatively generic complexes that catalyze DNA methylation and various types of histone modifications. There is increasing evidence that these complexes are directed to their sites of action by long non-protein-coding RNAs (lncRNAs), of which there are tens if not hundreds of thousands specified in the genome. LncRNAs are transcribed in complex intergenic, overlapping and antisense patterns relative to adjacent protein-coding genes, suggesting that many lncRNAs regulate the expression of these genes. LncRNAs also participate in a wide array of subcellular processes, including the formation and function of cellular organelles. Most lncRNAs are transcribed in a developmentally regulated and cell type specific manner, particularly in the CNS, wherein over half of all lncRNAs are expressed. While the numerous biological functions of lncRNAs are yet to be characterized fully, a number of recent studies suggest that lnRNAs are important for mediating cell identity. This function seems to be especially important for generating the enormous array of regional neuronal and glial cell subtypes that are present in the CNS. Further studies have also begun to elucidate additional roles played by lncRNAs in CNS processes, including homeostasis, stress responses and plasticity. Herein, we review emerging evidence that highlights the expression and function of lncRNAs in the CNS and suggests that lncRNA deregulation is an important factor in various CNS pathologies including neurodevelopmental, neurodegenerative and neuroimmunological disorders, primary brain tumors, and psychiatric diseases.

Figure 1. Illustrative examples of regionally enriched long non-coding RNA expression profiles in adult mouse brain

(a) In situ hybridization and (b) expression views displaying expression levels (red - high, yellow - medium, green - low) for AK019375, which is broadly but preferentially expressed in the olfactory bulb, hippocampus, and cerebellar cortex. (c) In situ hybridization and (d) expression views for AK017599, which is enriched in multiple layers of the cerebral cortex. (e) In situ hybridization and (f) expression views for AK157548, which is enriched in hippocampal CA1-3 subregions and the dentate gyrus (DG). (g) In situ hybridization and (h) expression views for AK050124, which is enriched in the granule cell and Purkinje cell layers of the cerebellum (Images courtesy of the Allen Brain Atlas - Allen Institute for Brain Science, Seattle).