title: 5'RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy.
abstract: The transcriptome is subject to multiple changes during pathogenesis, including the use of alternate 5' start-sites 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 cardiomyopathy (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 genome-wide changes in 5' start-site usage that are associated with pathogenic phenotypes.
authors: Danos C
authors: DC
authors: Christodoulou
authors: Hiroko
authors: H
authors: Wakimoto
authors: Kenji
authors: K
authors: Onoue
authors: Seda
authors: S
authors: Eminaga
authors: Joshua M
authors: JM
authors: Gorham
authors: Steve R
authors: SR
authors: DePalma
authors: Daniel S
authors: DS
authors: Herman
authors: Polakit
authors: P
authors: Teekakirikul
authors: David A
authors: DA
authors: Conner
authors: David M
authors: DM
authors: McKean
authors: Andrea A
authors: AA
authors: Domenighetti
authors: Anton
authors: A
authors: Aboukhalil
authors: Stephen
authors: S
authors: Chang
authors: Gyan
authors: G
authors: Srivastava
authors: Barbara
authors: B
authors: McDonough
authors: Philip L
authors: PL
authors: De Jager
authors: Ju
authors: J
authors: Chen
authors: Martha L
authors: ML
authors: Bulyk
authors: Jochen D
authors: JD
authors: Muehlschlegel
authors: Christine E
authors: CE
authors: Seidman
authors: J G
authors: JG
authors: Seidman
mesh_terms: D024506:5' Flanking Region; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D018387:Codon, Initiator; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D060588:LIM Domain Proteins / Q000235:genetics*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D009124:Muscle Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D017423:Sequence Analysis, RNA; D059467:Transcriptome
chemical_list: D018387:Codon, Initiator; C486306:Fhl1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D018995:Myosin Heavy Chains