Rbfox2 function in RNA metabolism is impaired in hypoplastic left heart syndrome patient hearts

Sunil K. Verma, Vaibhav Deshmukh, Curtis A. Nutter, Elizabeth Jaworski, Wenhao Jin, Lalita Wadhwa, Joshua Abata, Marco Ricci, Joy Lincoln, James F. Martin, Gene W. Yeo, Neslihan Martinez

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Hypoplastic left heart syndrome (HLHS) is a fatal congenital heart disease in which the left side of the heart is underdeveloped, impairing the systemic circulation. Underdeveloped left ventricle exerts biomechanical stress on the right ventricle that can progress into heart failure. Genome-wide transcriptome changes have been identified at early stages in the right ventricle (RV) of infants with HLHS, although the molecular mechanisms remain unknown. Here, we demonstrate that the RNA binding protein Rbfox2, which is mutated in HLHS patients, is a contributor to transcriptome changes in HLHS patient RVs. Our results indicate that majority of transcripts differentially expressed in HLHS patient hearts have validated Rbfox2 binding sites. We show that Rbfox2 regulates mRNA levels of targets with 3'UTR binding sites contributing to aberrant gene expression in HLHS patients. Strikingly, the Rbfox2 nonsense mutation identified in HLHS patients truncates the protein, impairs its subcellular distribution and adversely affects its function in RNA metabolism. Overall, our findings uncover a novel role for Rbfox2 in controlling transcriptome in HLHS.

Original languageEnglish (US)
Article number30896
JournalScientific Reports
Volume6
DOIs
StatePublished - Aug 3 2016

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Hypoplastic Left Heart Syndrome
RNA
Transcriptome
Heart Ventricles
Binding Sites
RNA-Binding Proteins
Nonsense Codon
3' Untranslated Regions
Heart Diseases
Heart Failure
Genome
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • General

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Rbfox2 function in RNA metabolism is impaired in hypoplastic left heart syndrome patient hearts. / Verma, Sunil K.; Deshmukh, Vaibhav; Nutter, Curtis A.; Jaworski, Elizabeth; Jin, Wenhao; Wadhwa, Lalita; Abata, Joshua; Ricci, Marco; Lincoln, Joy; Martin, James F.; Yeo, Gene W.; Martinez, Neslihan.

In: Scientific Reports, Vol. 6, 30896, 03.08.2016.

Research output: Contribution to journalArticle

Verma, SK, Deshmukh, V, Nutter, CA, Jaworski, E, Jin, W, Wadhwa, L, Abata, J, Ricci, M, Lincoln, J, Martin, JF, Yeo, GW & Martinez, N 2016, 'Rbfox2 function in RNA metabolism is impaired in hypoplastic left heart syndrome patient hearts', Scientific Reports, vol. 6, 30896. https://doi.org/10.1038/srep30896
Verma, Sunil K. ; Deshmukh, Vaibhav ; Nutter, Curtis A. ; Jaworski, Elizabeth ; Jin, Wenhao ; Wadhwa, Lalita ; Abata, Joshua ; Ricci, Marco ; Lincoln, Joy ; Martin, James F. ; Yeo, Gene W. ; Martinez, Neslihan. / Rbfox2 function in RNA metabolism is impaired in hypoplastic left heart syndrome patient hearts. In: Scientific Reports. 2016 ; Vol. 6.
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