Assessment of the Cardiac Noncoding Transcriptome by Single-Cell RNA Sequencing Identifies FIXER , a Conserved Profibrogenic Long Noncoding RNA
Year: 2023
Type: article
Abstract: BACKGROUND: Cardiac fibroblasts have crucial roles in the heart. In particular, fibroblasts differentiate into myofibroblasts in the damaged myocardium, contributing to scar formation and interstitial fibrosis. Fibrosis is associated with heart dysfunction and failure. Myofibroblasts therefore represent attractive therapeutic targets. However, the lack of myofibroblast-specific markers has precluded the development of targeted therapies. In this context, most of the noncoding genome is transcribed into long noncoding RNAs (lncRNAs). A number of lncRNAs have pivotal functions in the cardiovascular system. lncRNAs are globally more cell-specific than protein-coding genes, supporting their importance as key determinants of cell identity. METHODS: In this study, we evaluated the value of the lncRNA transcriptome in very deep single-cell RNA sequencing. We profiled the lncRNA transcriptome in cardiac nonmyocyte cells after infarction and probed heterogeneity in the fibroblast and myofibroblast populations. In addition, we searched for subpopulation-specific markers that can constitute novel targets in therapy for heart disease. RESULTS: We demonstrated that cardiac cell identity can be defined by the sole expression of lncRNAs in single-cell experiments. In this analysis, we identified lncRNAs enriched in relevant myofibroblast subpopulations. Selecting 1 candidate we named FIXER (fibrogenic LOX -locus enhancer RNA), we showed that its silencing limits fibrosis and improves heart function after infarction. Mechanitically, FIXER interacts with CBX4, an E3 SUMO protein ligase and transcription factor, guiding CBX4 to the promoter of the transcription factor RUNX1 to control its expression and, consequently, the expression of a fibrogenic gene program.. FIXER is conserved in humans, supporting its translational value. CONCLUSIONS: Our results demonstrated that lncRNA expression is sufficient to identify the various cell types composing the mammalian heart. Focusing on cardiac fibroblasts and their derivatives, we identified lncRNAs uniquely expressed in myofibroblasts. In particular, the lncRNA FIXER represents a novel therapeutic target for cardiac fibrosis.
Source: Circulation
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: National Science Foundation, National Institute for Health and Care Research, British Heart Foundation, University College London, European Commission, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Universidad de Navarra, Université de Lausanne, Horizon 2020 Framework Programme, Instituto de Salud Carlos III, European Regional Development Fund
Awards: G1889695962, MiCrovasculaR rarefaction in vascUlar Cognitive Impairement and heArt faiLure, G2441756889, G2628364946, Regenerative strategies for heart disease via targeting the long noncoding transcriptome, G3545278169, G4759803188, G4937468798, G5512256178, Efectos de la inhibición del cotransportador sodio-glucosa-2 sobre los mecanismos de daño cardiaco en el paciente diabético con insuficiencia cardiaca y fracción de eyección preservada., Evaluación personalizada del riesgo cardioembólico -1 (PACER-1), Single-cell analysis of long noncoding RNA-mediated transcriptomic perturbations in cardiac fibroblasts, Mechanisms of excess risk in Aortic STEnosis after valve Replacement (MASTER), G8824911526
OpenAlex ID: W4383710412