title: Functional importance of cardiac enhancer-associated noncoding RNAs in heart development and disease.
abstract: The key information processing units within gene regulatory networks are enhancers. Enhancer activity is associated with the production of tissue-specific noncoding RNAs, yet the existence of such transcripts during cardiac development has not been established. Using an integrated genomic approach, we demonstrate that fetal cardiac enhancers generate long noncoding RNAs (lncRNAs) during cardiac differentiation and morphogenesis. Enhancer expression correlates with the emergence of active enhancer chromatin states, the initiation of RNA polymerase II at enhancer loci and expression of target genes. Orthologous human sequences are also transcribed in fetal human hearts and cardiac progenitor cells. Through a systematic bioinformatic analysis, we identified and characterized, for the first time, a catalog of lncRNAs that are expressed during embryonic stem cell differentiation into cardiomyocytes and associated with active cardiac enhancer sequences. RNA-sequencing demonstrates that many of these transcripts are polyadenylated, multi-exonic long noncoding RNAs. Moreover, knockdown of two enhancer-associated lncRNAs resulted in the specific downregulation of their predicted target genes. Interestingly, the reactivation of the fetal gene program, a hallmark of the stress response in the adult heart, is accompanied by increased expression of fetal cardiac enhancer transcripts. Altogether, these findings demonstrate that the activity of cardiac enhancers and expression of their target genes are associated with the production of enhancer-derived lncRNAs.
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland. Electronic address: samir.ounzain@chuv.ch.
authors.forename: Samir
authors.initials: S
authors.lastname: Ounzain
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Iole
authors.initials: I
authors.lastname: Pezzuto
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Rudi
authors.initials: R
authors.lastname: Micheletti
authors.affiliation: VitalIT, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Burdet
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Razan
authors.initials: R
authors.lastname: Sheta
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Nemir
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Gonzales
authors.affiliation: Cardiovascular Assessment Facility, University of Lausanne, Lausanne, Switzerland.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Sarre
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Alexanian
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; US Department of Energy Joint Genome Institute, Walnut Creek, CA, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Blow
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; US Department of Energy Joint Genome Institute, Walnut Creek, CA, USA.
authors.forename: Dalit
authors.initials: D
authors.lastname: May
authors.affiliation: Bioinformatics and Genomics Group, Centre for Genomic Regulation, Barcelona, Spain.
authors.forename: Rory
authors.initials: R
authors.lastname: Johnson
authors.affiliation: VitalIT, Swiss Institute of Bioinformatics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Dauvillier
authors.affiliation: Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA; US Department of Energy Joint Genome Institute, Walnut Creek, CA, USA.
authors.forename: Len A
authors.initials: LA
authors.lastname: Pennacchio
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland. Electronic address: thierry.pedrazzini@chuv.ch.
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000502:physiology; D004742:Enhancer Elements, Genetic; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D006331:Heart Diseases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism; D061251:Primary Cell Culture; D062085:RNA, Long Noncoding / Q000502:physiology*
chemical_list: D009124:Muscle Proteins; D062085:RNA, Long Noncoding
keywords: Cardiac development; Enhancers; Gene regulation; Gene regulatory networks; Heart failure; Long noncoding RNA (lncRNAs)