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

Hum Mol Genet. 2019 May 1;28(9):1414-1428. doi: 10.1093/hmg/ddy438.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Gene Expression Regulation
  • Humans
  • Multiple Sclerosis / genetics*
  • Neoplasms / genetics*
  • RNA Interference
  • RNA, Circular*
  • RNA, Long Noncoding / genetics*
  • Transcriptome*


  • MALAT1 long non-coding RNA, human
  • RNA, Circular
  • RNA, Long Noncoding