Transgenic mice; Human; Regeneration; Heart; Enhancer; Long noncoding RNAs; Physiology
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Alexanian Michael, Maric Daniel, Jenkinson Stephen P., Mina Marco, Friedman Clayton E., Ting Ching-Chia, Micheletti Rudi, Plaisance Isabelle, Nemir Mohamed, Maison Damien, Kernen Jasmin, Pezzuto Iole, Villeneuve Dominic, Burdet Frédéric, Ibberson Mark, Leib Stephen L., Palpant Nathan J., Hernandez Nouria, Ounzain Samir, Pedrazzini Thierry (2017), A transcribed enhancer dictates mesendoderm specification in pluripotency, in Nature Communications
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Micheletti Rudi, Plaisance Isabelle, Abraham Brian J., Sarre Alexandre, Ting Ching-Chia, Alexanian Michael, Maric Daniel, Maison Damien, Nemir Mohamed, Young Richard A., Schroen Blanche, González Arantxa, Ounzain Samir, Pedrazzini Thierry (2017), The long noncoding RNA Wisper controls cardiac fibrosis and remodeling, in Science Translational Medicine
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Alexanian Michael, Pedrazzini Thierry, Ounzain Samir (2017), New Lncs to mesendoderm specification, in Journal of Thoracic Disease
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Plaisance Isabelle, Perruchoud Stéphanie, Fernandez-Tenorio Miguel, Gonzales Christine, Ounzain Samir, Ruchat Patrick, Nemir Mohamed, Niggli Ernst, Pedrazzini Thierry (2016), Cardiomyocyte Lineage Specification in Adult Human Cardiac Precursor Cells Via Modulation of Enhancer-Associated Long Noncoding RNA Expression, in JACC: Basic to Translational Science
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Ounzain Samir, Pedrazzini Thierry (2016), Long non-coding RNAs in heart failure: a promising future with much to learn, in Annals of Translational Medicine
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Ounzain Samir, Pedrazzini Thierry (2016), Super-enhancer lnc s to cardiovascular development and disease, in Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
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Ounzain Samir, Pedrazzini Thierry (2016), Divergent Paths Lnc Cell Fates, in Cell Stem Cell
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Crippa Stefania, Nemir Mohamed, Ounzain Samir, Ibberson Mark, Berthonneche Corinne, Sarre Alexandre, Boisset Gaëlle, Maison Damien, Harshman Keith, Xenarios Ioannis, Diviani Dario, Schorderet Daniel, Pedrazzini Thierry (2016), Comparative transcriptome profiling of the injured zebrafish and mouse hearts identifies miRNA-dependent repair pathways, in Cardiovascular Research
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Shende Pankaj, Xu Lifen, Morandi Christian, Pentassuglia Laura, Heim Philippe, Lebboukh Sonia, Berthonneche Corinne, Pedrazzini Thierry, Kaufmann Beat A., Hall Michael N., Rüegg Markus A., Brink Marijke (2015), Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy, in Cardiovascular Research
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Ounzain Samir, Micheletti Rudi, Arnan Carme, Plaisance Isabelle, Cecchi Dario, Schroen Blanche, Reverter Ferran, Alexanian Michael, Gonzales Christine, Ng Shi Yan, Bussotti Giovanni, Pezzuto Iole, Notredame Cedric, Heymans Stephane, Guigó Roderic, Johnson Rory, Pedrazzini Thierry (2015), CARMEN, a human super enhancer-associated long noncoding RNA controlling cardiac specification, differentiation and homeostasis, in Journal of Molecular and Cellular Cardiology
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In the Western world, cardiovascular diseases represent a major cause of mortality and morbidity. Heart failure in particular is evolving into a global epidemic. Despite the development of new therapies, no approaches currently exist to reverse the loss of cardiomyocytes in the failing heart. The only option for end-stage heart failure remains heart transplantation, which is limited due to the increased demand and scarcity of donor hearts. Medicine is therefore in need of rapid innovation. In this context, one area that has engendered considerable interest over the last decade is the premise of inducing regeneration in the damaged heart. Cardiac myocytes could be reprogrammed in situ to reenter the cell cycle. In addition, cardiac precursor cells could be manipulated to favor conversion into functional cardiomyocytes. Both strategies aim at producing newly formed cardiomyocytes.Long noncoding RNAs (lncRNAs) represent a class of RNAs with no apparent protein-coding potential. LncRNAs are emerging as master regulators of gene expression. LncRNAs appear to function during development to repress non-appropriate gene networks through the recruitment of repressive chromatin modifying complexes. In addition, lncRNAs, which are transcribed from active enhancer sequences (enhancer-associated lncRNAs), contribute to neighboring gene activation via cis-mechanisms.In the heart, lncRNAs are emerging as key regulators of programming and reprogramming of cardiac cells during development and in adulthood. In a first study, we have used very deep RNA sequencing to profile the noncoding transcriptome in the mouse heart after myocardial infarction. We have identified 1500 novel lncRNAs via RNA Seq and ab initio reconstruction. We also integrated publically available genome-wide data sets to functionally characterize lncRNAs and associate them with specific cardiac pathological processes. The vast majority of newly discovered heart-specific lncRNAs were predominantly derived from enhancer sequences. More recently, we have applied this strategy to analysis various lncRNA transcriptomes in mouse embryonic stem cells or human cardiac precursor cells differentiating into cardiomyocytes. We have therefore generated several catalogs of novel lncRNAs, which contains hundreds of candidates and can be screened for identifying lncRNAs demonstrating functional importance during cardiac cell programming and reprogramming.Our main objective is therefore to identify lncRNAs from our catalogs, which could be targeted to induce adult mouse cardiomyocyte proliferation and/or cardiogenic differentiation in human cardiac precursor cells. We will first bioinformatically preselect candidates from the lncRNA catalogs based on predicted function in relevant biological situations. We will next design modified antisense oligonucleotide inhibitors (GapmeRs) to specifically target the selected lncRNAs. GapmeRs will be systematically evaluated for their capacity to induce reprogramming in high throughput functional assays. We propose to deplete lncRNAs to alleviate repression of particular states, and facilitate reprogramming. Therapeutic depletion of candidate lncRNAs is indeed desirable for both biological and technical reasons. In addition, because of the stringent selection of candidate lncRNAs, GapmeR-based therapies will target only highly cell-specific lncRNAs. Off-target effects are de facto excluded because no cell types are expected to express the targeted lncRNAs, making these therapeutic agents ideal for translation in the clinic. Thus, experiments will be designed to validate in vivo findings obtained from functional screens performed in vitro, and evaluate the capacity of identified GapmeRs to induce regeneration in the adult heart.