title: CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis.
abstract: Long noncoding RNAs (lncRNAs) are emerging as important regulators of developmental pathways. However, their roles in human cardiac precursor cell (CPC) remain unexplored. To characterize the long noncoding transcriptome during human CPC cardiac differentiation, we profiled the lncRNA transcriptome in CPCs isolated from the human fetal heart and identified 570 lncRNAs that were modulated during cardiac differentiation. Many of these were associated with active cardiac enhancer and super enhancers (SE) with their expression being correlated with proximal cardiac genes. One of the most upregulated lncRNAs was a SE-associated lncRNA that was named CARMEN, (CAR)diac (M)esoderm (E)nhancer-associated (N)oncoding RNA. CARMEN exhibits RNA-dependent enhancing activity and is upstream of the cardiac mesoderm-specifying gene regulatory network. Interestingly, CARMEN interacts with SUZ12 and EZH2, two components of the polycomb repressive complex 2 (PRC2). We demonstrate that CARMEN knockdown inhibits cardiac specification and differentiation in cardiac precursor cells independently of MIR-143 and -145 expression, two microRNAs located proximal to the enhancer sequences. Importantly, CARMEN expression was activated during pathological remodeling in the mouse and human hearts, and was necessary for maintaining cardiac identity in differentiated cardiomyocytes. This study demonstrates therefore that CARMEN is a crucial regulator of cardiac cell differentiation and homeostasis.
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: Rudi
authors.initials: R
authors.lastname: Micheletti
authors.affiliation: Bioinformatics and Genomics Group, Centre for Genomic Regulation, Barcelona, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Arnan
authors.affiliation: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Plaisance
authors.affiliation: Bioinformatics and Genomics Group, Centre for Genomic Regulation, Barcelona, Spain.
authors.forename: Dario
authors.initials: D
authors.lastname: Cecchi
authors.affiliation: Centre for Heart Failure Research, Cardiovascular Research Institute, Maastricht University, The Netherlands.
authors.forename: Blanche
authors.initials: B
authors.lastname: Schroen
authors.affiliation: Bioinformatics and Genomics Group, Centre for Genomic Regulation, Barcelona, Spain.
authors.forename: Ferran
authors.initials: F
authors.lastname: Reverter
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: Experimental Cardiology Unit, Department of Medicine, University of Lausanne Medical School, Lausanne, Switzerland.
authors.forename: Christine
authors.initials: C
authors.lastname: Gonzales
authors.affiliation: Stem Cell and Developmental Biology Group, Genome Institute of Singapore, Singapore; NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
authors.forename: Shi Yan
authors.initials: SY
authors.lastname: Ng
authors.affiliation: Comparative Bioinformatics Group, Centre for Genomic Regulation, Barcelona, Spain.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bussotti
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: Comparative Bioinformatics Group, Centre for Genomic Regulation, Barcelona, Spain.
authors.forename: Cedric
authors.initials: C
authors.lastname: Notredame
authors.affiliation: Centre for Heart Failure Research, Cardiovascular Research Institute, Maastricht University, The Netherlands.
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.affiliation: Bioinformatics and Genomics Group, Centre for Genomic Regulation, Barcelona, Spain.
authors.forename: Roderic
authors.initials: R
authors.lastname: Guigó
authors.affiliation: Bioinformatics and Genomics Group, Centre for Genomic Regulation, Barcelona, Spain. Electronic address: rory.johnson@crg.es.
authors.forename: Rory
authors.initials: R
authors.lastname: Johnson
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; D019521:Body Patterning / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006321:Heart / Q000196:embryology*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D051379:Mice; D009206:Myocardium / Q000473:pathology; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology; D059467:Transcriptome / Q000235:genetics
chemical_list: D062085:RNA, Long Noncoding; C494163:Suz12 protein, mouse; C000611219:long non-coding RNA CARMEN, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2
keywords: Cardiac development; Cardiac precursor cells; Gene regulation; Heart failure; Long noncoding RNA; Super enhancer