Exploring the pleiotropic effects of lncRNA in different repeat expansion disorders

Abstract

Long non-coding RNAs (lncRNAs), once considered “junk, “have emerged as crucial modulators of several biological processes, including gene expression and epigenetic modifications. Advances in RNA sequencing have demonstrated their widespread role in various diseases, including repeat expansion disorders (REDs), which result from unusual expansions of simple sequence repeats. These expansions contribute to a cascade of molecular disruptions, including transcriptional silencing, RNA-protein interactions, and abnormal protein translation, which collectively contribute to the complex pathophysiology of the diseases. Contrary to the conventional perception of REDs as exclusively hereditary disorders, recent studies have shown that lncRNAs can influence the development of different REDs. In this review, we highlight the dynamic role of four crucial lncRNAs in the context of REDs: nuclear paraspeckle assembly transcript 1 (NEAT1), taurine upregulated gene 1 (TUG1), maternally expressed gene 3 (MEG3), and metastasis associated lung adenocarcinoma transcript 1 (MALAT1), which have demonstrated their involvement in multiple REDs through the modulation of diverse biochemical pathways. Despite their potential as therapeutic targets and diagnostic biomarkers, the clinical application of lncRNAs is limited due to their immunogenicity, delivery challenges, and specificity. By investigating the overall etiology and remaining challenges, we intend to shed light on how modifying lncRNA activity could open up novel treatment avenues for REDs. © 2025 Elsevier B.V., All rights reserved.