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

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

Research output: Contribution to journalArticlepeer-review

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
JournalRNA Biology
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • Boltzmann ensemble
  • cardiovascular disease
  • H19
  • lncRNA
  • minimum free energy
  • RiboSNitch
  • RNA structure
  • rs217727
  • SHAPE-Seq
  • SNP

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'A genetic variant alters the secondary structure of the lncRNA H19 and is associated with dilated cardiomyopathy'. Together they form a unique fingerprint.

Cite this