Not only cancer: the long non-coding RNA MALAT1 affects the repertoire of alternatively spliced transcripts and circular RNAs in multiple sclerosis

Authors

Giulia Cardamone, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy.
Elvezia M. Paraboschi, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy.
Giulia Soldà, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy.
Claudia Cantoni, Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.Follow
Domenico Supino, Humanitas Clinical and Research Center, Rozzano Milan, Italy.
Laura Piccio, Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
Stefano Duga, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy.
Rosanna Asselta, Department of Biomedical Sciences, Humanitas University, Pieve Emanuele Milan, Italy.

Document Type

Article

Abstract

Long non-coding RNAs (lncRNAs) are post-transcriptional and epigenetic regulators, whose implication in neurodegenerative and autoimmune diseases remains poorly understood. We analyzed publicly available microarray data sets to identify dysregulated lncRNAs in multiple sclerosis (MS), a neuroinflammatory autoimmune disease. We found a consistent upregulation in MS of the lncRNA MALAT1 (2.7-fold increase; meta-analysis, P = 1.3 × 10-8; 190 cases, 182 controls), known to regulate alternative splicing (AS). We confirmed MALAT1 upregulation in two independent MS cohorts (1.5-fold increase; P < 0.01; 59 cases, 50 controls). We hence performed MALAT1 overexpression/knockdown in cell lines, demonstrating that its modulation impacts on endogenous expression of splicing factors (HNRNPF and HNRNPH1) and on AS of MS-associated genes (IL7R and SP140). Minigene-based splicing assays upon MALAT1 modulation recapitulated IL7R and SP140 isoform unbalances observed in patients. RNA-sequencing of MALAT1-knockdown Jurkat cells further highlighted MALAT1 role in splicing (approximately 1100 significantly-modulated AS events) and revealed its contribution to backsplicing (approximately 50 differentially expressed circular RNAs). Our study proposes a possible novel role for MALAT1 dysregulation and the consequent AS alteration in MS pathogenesis, based on anomalous splicing/backsplicing profiles of MS-relevant genes.

Medical Subject Headings

Alternative Splicing; Gene Expression Regulation; Humans; Multiple Sclerosis (genetics); Neoplasms (genetics); RNA Interference; RNA, Circular; RNA, Long Noncoding (genetics); Transcriptome

Publication Date

5-1-2019

Publication Title

Human molecular genetics

E-ISSN

1460-2083

Volume

28

Issue

9

First Page

1414

Last Page

1428

PubMed ID

30566690

Digital Object Identifier (DOI)

10.1093/hmg/ddy438

Recommended Citation

Cardamone, Giulia; Paraboschi, Elvezia M.; Soldà, Giulia; Cantoni, Claudia; Supino, Domenico; Piccio, Laura; Duga, Stefano; and Asselta, Rosanna, "Not only cancer: the long non-coding RNA MALAT1 affects the repertoire of alternatively spliced transcripts and circular RNAs in multiple sclerosis" (2019). Translational Neuroscience. 2339.
https://scholar.barrowneuro.org/neurobiology/2339