Rbm20-deficient cardiogenesis reveals early disruption of RNA processing and sarcomere remodeling establishing a developmental etiology for dilated cardiomyopathy

Rosanna Beraldi, Xing Li, Almudena Martinez Fernandez, Santiago Reyes, Frank Secreto, Andre Terzic, Timothy M. Olson, Timothy J. Nelson

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Dilated cardiomyopathy (DCM) due to mutations in RBM20, a gene encoding an RNA-binding protein, is associated with high familial penetrance, risk of progressive heart failure and sudden death. Although genetic investigations and physiologicalmodels have established the linkage ofRBM20with early-onsetDCM, the underlying basis of cellularandmolecular dysfunction is undetermined.Modelinghumangenetics using a high-throughput pluripotent stem cell platform was herein designed to pinpoint the initial transcriptome dysfunction and mechanistic corruption in disease pathogenesis. Tnnt2-pGreenZeo pluripotent stem cells were engineered to knockdown Rbm20 (shRbm20) to determine the cardiac-pathogenic phenotype during cardiac differentiation. Intracellular Ca2+ transients revealed Rbm20-dependent alteration in Ca2+ handling, coinciding with known pathological splice variants of Titin and Camk2d genes by Day 24 of cardiogenesis. Ultrastructural analysis demonstrated elongated and thinner sarcomeres in the absence ofRbm20 that is consistent withhumancardiac biopsy samples. Furthermore, Rbm20-depleted transcriptional profiling at Day 12 identified Rbm20-dependent dysregulation with 76% of differentially expressed genes linked to known cardiac pathology ranging from primordial Nkx2.5 to mature cardiac Tnnt2 as the initial molecular aberrations. Notably, downstream consequences of Rbm20-depletion at Day 24 of differentiation demonstrated significant dysregulation of extracellular matrix components such as the anomalous overexpression of the Vtn gene. By using the pluripotent stem cell platform tomodelhuman cardiac disease according to a stage-specific cardiogenic roadmap, weestablished a newparadigm of familialDCMpathogenesis as a developmental disorder that is patterned duringearly cardiogenesis and propagated with cellular mechanisms of pathological cardiac remodeling.

Original languageEnglish (US)
Article numberddu091
Pages (from-to)3779-3791
Number of pages13
JournalHuman molecular genetics
Volume23
Issue number14
DOIs
StatePublished - Jul 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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