5'RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy

Danos C. Christodoulou, Hiroko Wakimoto, Kenji Onoue, Seda Eminaga, Joshua M. Gorham, Steve R. DePalma, Daniel S. Herman, Polakit Teekakirikul, David A. Conner, David M. McKean, Andrea A. Domenighetti, Anton Aboukhalil, Stephen Chang, Gyan Srivastava, Barbara McDonough, Philip L. De Jager, Ju Chen, Martha L. Bulyk, Jochen D. Muehlschlege, Christine E. Seidman*J. G. Seidman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

Abstract

The transcriptome is subject to multiple changes during pathogenesis, including the use of alternate 5' startsites that can affect transcription levels and output. Current RNA sequencing techniques can assess mRNA levels, but do not robustly detect changes in 5' start-site use. Here, we developed a transcriptome sequencing strategy that detects genome-wide changes in start-site usage (5'RNA-Seq) and applied this methodology to identify regulatory events that occur in hypertrophic carcliomyopathy (HCM). Compared with transcripts from WT mice, 92 genes had altered start-site usage in a mouse model of HCM, including four-and-a-half LIM domains protein 1 (Fhl1). HCM-induced altered transcriptional regulation of Fhl1 resulted in robust myocyte expression of a distinct protein isoform, a response that was conserved in humans with genetic or acquired cardiomyopathies. Genetic ablation of Fhl1 in HCM mice was deleterious, which suggests that Fhl1 transcriptional changes provide salutary effects on stressed myocytes in this disease. Because Fhl1 is a chromosome X-encoded gene, stress-induced changes in its transcription may contribute to gender differences in the clinical severity of HCM. Our findings indicate that 5'RNA-Seq has the potential to identify gen omewide changes in 5' start-site usage that are associated with pathogenic phenotypes.

Original languageEnglish
Pages (from-to)1364-1370
Number of pages7
JournalJournal of Clinical Investigation
Volume124
Issue number3
Early online date10 Feb 2014
DOIs
Publication statusPublished - 3 Mar 2014

Keywords

  • FAMILIAL HYPERTROPHIC CARDIOMYOPATHY
  • RNA-SEQ
  • CARDIAC FIBROSIS
  • MESSENGER-RNA
  • EXPRESSION
  • BETA
  • TRANSCRIPT
  • RESPONSES
  • MUTATION
  • TOPHAT

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