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.

Regulatory Potential of Competing Endogenous RNAs in Myotonic Dystrophies

“…Regarding putative perturbations in raceRNA crosstalk and relevance of miRNA sponging in the pathogenesis of DM, further studies are needed to explain whether the presence of expanded repeats and aberrant expression of certain ceRNAs are interrelated. Interestingly, it was recently reported that functional mechanisms of lncRNAs and the potential pathogenic mechanisms of expanded microsatellite RNA may be linked [ 9 ]. Shared mechanisms include protein sequestration, peptide translation, miRNA processing and miRNA sequestration.…”

“…There is growing evidence that, in pathology, the RNA communication system is disrupted [ 2 , 4 , 5 , 6 , 7 , 8 ]. It was also suggested that such communication between RNA molecules may play an important role in various repeat-associated diseases [ 9 , 10 ]. The common denominator of the repeat-associated diseases is a special mutation in relevant genes, where short nucleotide sequences are repeated many times and form unusually long tracts of repeats.…”

“…It was proposed that repeat-associated ceRNAs (raceRNAs) characteristic of two neuromuscular diseases, namely, myotonic dystrophy type 1 and 2 (DM1 and DM2), may cooperate in their regulatory functions. Importantly, it has been shown that numerous miRNAs may bind to simple sequence repeats present in toxic RNAs and there are several reports addressing potential RNA cross-regulation in repeat-associated diseases [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Given that DM1 and DM2 are neuromuscular diseases, it seems additionally interesting to examine functional ncRNAs from the perspective of nervous and muscle cells, as the importance of ceRNA crosstalk in these tissues has been addressed [ 5 , 15 ].…”

Enhanced detection of nucleotide repeat mRNA with hybridization chain reaction

“…Repeats as DNA can inhibit transcription of repeat-containing genes and promote the DNA damage response through R-loop formation (Tuduri et al 2009;Reddy et al 2011;Reddy et al 2014;Groh et al 2014;Haeusler et al 2014). Repeats as RNA can functionally sequester both canonical and non-canonical RNA binding proteins and prevent them from performing their normal functions (Miller et al 2000;Mankodi et al 2000;Jin et al 2007;Cooper-Knock et al 2014;Conlon et al 2016;Lee et al 2013; reviewed in Rodriguez and Todd 2019;Swinnen, Robberecht, and Van Den Bosch 2020;Johnson and Cooper 2021). Repeats can also be translated into toxic proteins, either via canonical translation (as occurs for a number of polyglutamine expansions) or via repeat associated non-AUG (RAN) initiated translation (Zu et al 2011;Todd et al 2013;Green et al 2017;Kearse et al 2016;Paulson et al 1997;Trottier et al 1995;La Spada et al 1991).…”

“…These foci are thought to represent repeat RNAs coassociated with specific RNA binding proteins, although they may also arise from intraand inter-molecular RNA-RNA interactions via RNA gelation (Jain and Vale 2017;Fay, Anderson, and Ivanov 2017;Mankodi et al 2001;Fardaei et al 2002;Tassone, Iwahashi, and Hagerman 2004;Iwahashi et al 2006;Jin et al 2007;Sofola et al 2007;Sellier et al 2010;Sellier et al 2013;Bajc Cesnik et al 2019). The exact behavior, biophysical properties, and associated protein and RNA factors of these RNA condensates varies across different repeat expansions (reviewed in Nussbacher et al 2019; Echeverria and Cooper 2012;Johnson and Cooper 2021). Traditionally, these foci are visualized by fluorescent in situ hybridization (FISH) ( Figure 1A) (Urbanek and Krzyzosiak 2016;Lee et al 2013;Urbanek, Michalak, and Krzyzosiak 2017;Hoem et al 2011;Verma et al 2019;Jin et al 2007).…”