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

doi:10.1172/JCI70108

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

Cardiovascular Sciences

Research output: Contribution to journal › Article › peer-review

53 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 language	English
Pages (from-to)	1364-1370
Number of pages	7
Journal	Journal of Clinical Investigation
Volume	124
Issue number	3
Early online date	10 Feb 2014
DOIs	https://doi.org/10.1172/JCI70108
Publication status	Published - 3 Mar 2014

Keywords

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

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10.1172/JCI70108

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Christodoulou, D. C., Wakimoto, H., Onoue, K., Eminaga, S., Gorham, J. M., DePalma, S. R., Herman, D. S., Teekakirikul, P., Conner, D. A., McKean, D. M., Domenighetti, A. A., Aboukhalil, A., Chang, S., Srivastava, G., McDonough, B., De Jager, P. L., Chen, J., Bulyk, M. L., Muehlschlege, J. D., ... Seidman, J. G. (2014). 5'RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy. Journal of Clinical Investigation, 124(3), 1364-1370. https://doi.org/10.1172/JCI70108

@article{e8eb516180464e5eb401b85784ff81ae,

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' 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.",

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

year = "2014",

month = mar,

day = "3",

doi = "10.1172/JCI70108",

language = "English",

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Christodoulou, DC, Wakimoto, H, Onoue, K, Eminaga, S, Gorham, JM, DePalma, SR, Herman, DS, Teekakirikul, P, Conner, DA, McKean, DM, Domenighetti, AA, Aboukhalil, A, Chang, S, Srivastava, G, McDonough, B, De Jager, PL, Chen, J, Bulyk, ML, Muehlschlege, JD, Seidman, CE & Seidman, JG 2014, '5'RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy', Journal of Clinical Investigation, vol. 124, no. 3, pp. 1364-1370. https://doi.org/10.1172/JCI70108

TY - JOUR

T1 - 5'RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy

AU - Christodoulou, Danos C.

AU - Wakimoto, Hiroko

AU - Onoue, Kenji

AU - Eminaga, Seda

AU - Gorham, Joshua M.

AU - DePalma, Steve R.

AU - Herman, Daniel S.

AU - Teekakirikul, Polakit

AU - Conner, David A.

AU - McKean, David M.

AU - Domenighetti, Andrea A.

AU - Aboukhalil, Anton

AU - Chang, Stephen

AU - Srivastava, Gyan

AU - McDonough, Barbara

AU - De Jager, Philip L.

AU - Chen, Ju

AU - Bulyk, Martha L.

AU - Muehlschlege, Jochen D.

AU - Seidman, Christine E.

AU - Seidman, J. G.

PY - 2014/3/3

Y1 - 2014/3/3

N2 - 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.

AB - 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.

KW - FAMILIAL HYPERTROPHIC CARDIOMYOPATHY

KW - RNA-SEQ

KW - CARDIAC FIBROSIS

KW - MESSENGER-RNA

KW - EXPRESSION

KW - BETA

KW - TRANSCRIPT

KW - RESPONSES

KW - MUTATION

KW - TOPHAT

U2 - 10.1172/JCI70108

DO - 10.1172/JCI70108

M3 - Article

SN - 0021-9738

VL - 124

SP - 1364

EP - 1370

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 3

ER -

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

Abstract

Keywords

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