A genetic variant alters the secondary structure of the lncRNA H19 and is associated with dilated cardiomyopathy

Leonie Martens, Frank Ruehle, Anika Witten, Benjamin Meder, Hugo A. Katus, Eloisa Arbustini, Gerd Hasenfuss, Moritz F. Sinner, Stefan Kaeaeb, Sabine Pankuweit, Christiane Angermann, Erich Bornberg-Bauer, Monika Stoll*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Web of Science)

Abstract

lncRNAs are at the core of many regulatory processes and have also been recognized to be involved in various complex diseases. They affect gene regulation through direct interactions with RNA, DNA or proteins. Accordingly, lncRNA structure is likely to be essential for their regulatory function. Point mutations, which manifest as SNPs (single nucleotide polymorphisms) in genome screens, can substantially alter their function and, subsequently, the expression of their downstream regulated genes. To test the effect of SNPs on structure, we investigated lncRNAs associated with dilated cardiomyopathy. Among 322 human candidate lncRNAs, we demonstrate first the significant association of an SNP located in lncRNA H19 using data from 1084 diseased and 751 control patients. H19 is generally highly expressed in the heart, with a complex expression pattern during heart development. Next, we used MFE (minimum free energy) folding to demonstrate a significant refolding in the secondary structure of this 861 nt long lncRNA. Since MFE folding may overlook the importance of sub-optimal structures, we showed that this refolding also manifests in the overall Boltzmann structure ensemble. There, the composition of structures is tremendously affected in their thermodynamic probabilities through the genetic variant. Finally, we confirmed these results experimentally, using SHAPE-Seq, corroborating that SNPs affecting such structures may explain hidden genetic variance not accounted for through genome wide association studies. Our results suggest that structural changes in lncRNAs, and lncRNA H19 in particular, affect regulatory processes and represent optimal targets for further in-depth studies probing their molecular interactions.

Original languageEnglish
Pages (from-to)409-415
Number of pages7
JournalRna Biology
Volume18
Early online date29 Jul 2021
DOIs
Publication statusPublished - 15 Oct 2021

Keywords

  • RNA structure
  • lncRNA
  • cardiovascular disease
  • RiboSNitch
  • Boltzmann ensemble
  • minimum free energy
  • SHAPE-Seq
  • H19
  • rs217727
  • SNP
  • LONG NONCODING RNA
  • LANDSCAPE
  • EVOLUTION
  • DISEASE
  • AXIS

Cite this