Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long non-coding RNAs.
OBJECTIVE
Heart disease is recognized as a consequence of dysregulation of cardiac gene regulatory networks. Previously, unappreciated components of such networks are the long non-coding RNAs (lncRNAs). Their roles in the heart remain to be elucidated. Thus, this study aimed to systematically characterize the cardiac long non-coding transcriptome post-myocardial infarction and to elucidate their potential roles in cardiac homoeostasis.


RESULTS
We annotated the mouse transcriptome after myocardial infarction via RNA sequencing and ab initio transcript reconstruction, and integrated genome-wide approaches to associate specific lncRNAs with developmental processes and physiological parameters. Expression of specific lncRNAs strongly correlated with defined parameters of cardiac dimensions and function. Using chromatin maps to infer lncRNA function, we identified many with potential roles in cardiogenesis and pathological remodelling. The vast majority was associated with active cardiac-specific enhancers. Importantly, oligonucleotide-mediated knockdown implicated novel lncRNAs in controlling expression of key regulatory proteins involved in cardiogenesis. Finally, we identified hundreds of human orthologues and demonstrate that particular candidates were differentially modulated in human heart disease.


CONCLUSIONS
These findings reveal hundreds of novel heart-specific lncRNAs with unique regulatory and functional characteristics relevant to maladaptive remodelling, cardiac function and possibly cardiac regeneration. This new class of molecules represents potential therapeutic targets for cardiac disease. Furthermore, their exquisite correlation with cardiac physiology renders them attractive candidate biomarkers to be used in the clinic.
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland thierry.pedrazzini@chuv.ch.
Samir
S
Ounzain
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland.
Rudi
R
Micheletti
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland.
Tal
T
Beckmann
Centre for Heart Failure Research, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands.
Blanche
B
Schroen
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland.
Michael
M
Alexanian
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland.
Iole
I
Pezzuto
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland.
Stefania
S
Crippa
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland.
Mohamed
M
Nemir
Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland.
Alexandre
A
Sarre
Centre for Genomic Regulation, Barcelona, Spain.
Rory
R
Johnson
VitalIT, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
Jérôme
J
Dauvillier
VitalIT, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
Frédéric
F
Burdet
VitalIT, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
Mark
M
Ibberson
Centre for Genomic Regulation, Barcelona, Spain.
Roderic
R
Guigó
VitalIT, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
Ioannis
I
Xenarios
Centre for Heart Failure Research, Cardiovascular Research Institute, Maastricht University, Maastricht, The Netherlands.
Stephane
S
Heymans
Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, CH-1011 Lausanne, Switzerland thierry.pedrazzini@chuv.ch.
Thierry
T
Pedrazzini
D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics*; D014162:Transfection; D066253:Vascular Remodeling / Q000235:genetics
D015415:Biomarkers; D002843:Chromatin; D062085:RNA, Long Noncoding
Heart failure; Long non-coding RNAs; Myocardial infarction; Next-generation sequencing; Transcriptome