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.
Highlights
The RNA binding protein Rbfox[2] has been recently identified as a major risk allele for HLHS7
To determine regulators that account for abnormal gene expression in Hypoplastic left heart syndrome (HLHS) patient right ventricle (RV), we focused on the RNA binding protein Rbfox[2], because it was identified as a major risk allele for HLHS using a large cohort of congenital heart disease patients[7]
Mutations in certain genes are identified in HLHS patient tissues[29,30,31,32,33], yet underlying genetic, molecular and cellular events responsible for HLHS RV pathogenesis are not well understood
Summary
The RNA binding protein Rbfox[2] has been recently identified as a major risk allele for HLHS7. Rbfox[2] binding targets were identified in mouse and human ES cells and 293T cells using cross-linking immunoprecipitation followed by RNA-sequencing (CLIP-seq) analysis[10,11,12]. Conditional deletion of Rbfox[2] in the cerebellum leads to AS and developmental defects[16]. Knockdown of both Rbfox[2] and its paralog Rbfox[1] in zebrafish lowers heart rate and causes myofibrillar disarray[17]. We demonstrate that HLHS patient specific mutation in Rbfox[2] induces a dramatic change in Rbfox[2] protein subcellular localization and affects its function in RNA splicing. Our findings may allow identification of innovative therapy strategies such as the use of modified oligos or small molecules to restore Rbfox[2] function in patients with HLHS
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