Overlapping mechanisms of lncRNA and expanded microsatellite RNA

Abstract

RNA has major regulatory roles in a wide range of biological processes and a surge of RNA research has led to the classification of numerous functional RNA species. One example is long noncoding RNAs (lncRNAs) that are structurally complex transcripts >200 nucleotides (nt) in length and lacking a canonical open reading frame (ORF). Despite a general lack of sequence conservation and low expression levels, many lncRNAs have been shown to have functionality in diverse biological processes as well as in mechanisms of disease. In parallel with the growing understanding of lncRNA functions, there is a growing subset of microsatellite expansion disorders in which the primary mechanism of pathogenesis is an RNA gain of function arising from RNA transcripts from the mutant allele. Microsatellite expansion disorders are caused by an expansion of short (3-10 nt) repeats located within coding genes. Expanded repeat-containing RNA mediates toxicity through multiple mechanisms, the details of which remain only partially understood. The purpose of this review is to highlight the links between functional mechanisms of lncRNAs and the potential pathogenic mechanisms of expanded microsatellite RNA. These shared mechanisms include protein sequestration, peptide translation, micro-RNA (miRNA) processing, and miRNA sequestration. Recognizing the parallels between the normal functions of lncRNAs and the negative impact of expanded microsatellite RNA on biological processes can provide reciprocal understanding to the roles of both RNA species. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease.

Keywords: expanded microsatellite RNA; long noncoding RNA; miRNA; protein sequestration.

Figure 1.

LncRNAs and expanded microsatellite RNA display extensive functional overlap. Shared mechanisms include protein sequestration, peptide translation, miRNA processing, and miRNA sequestration. Understanding parallel mechanisms shared between the two RNA species can reveal biological impact relevant to both lncRNAs and pathogenic microsatellite RNAs. (Created with BioRender.com)

Figure 2.

Certain lncRNAs have been shown to exhibit phase separation capacity. A commonality between these lncRNA is the presence of repeat tracts. The lncRNA NEAT1 contains evolutionarily conserved UG repeat tracts which recruit proteins including FUS and NONO leading to paraspeckle formation. The lncRNA HSRω in D. Melanogaster encodes a 280bp repeat tract. Upon heat shock, the lncRNA localizes to its locus of origin and recruits hnRNP proteins leading to omega speckle formation at the gene locus. The lncRNA Xist, containing six conserved repeat tracts (the sequence of the repeats varies), has also been hypothesized to exhibit phase separation during X-chromosome inactivation by recruiting hnRNPs and paraspeckle proteins. Evidence suggests that expanded repeat RNA, specifically CUG and CCUG (the repeat expansions exhibited in DM1 and DM2, respectively), phase separates to form the pathogenic RNA foci. Whether proteins are required for this process is yet to be fully understood as there is evidence for both instances. (Created with BioRender.com)