Assessment of the Cardiac Noncoding Transcriptome by Single-Cell RNA Sequencing Identifies FIXER, a Conserved Profibrogenic Long Noncoding RNA.

Aghagolzadeh, Parisa; Plaisance, Isabelle; Bernasconi, Riccardo; Treibel, Thomas A; Pulido Quetglas, Carlos; Wyss, Tania; Wigger, Leonore; Nemir, Mohamed; Sarre, Alexandre; Chouvardas, Panagiotis; Johnson, Rory; González, Arantxa; Pedrazzini, Thierry (2023). Assessment of the Cardiac Noncoding Transcriptome by Single-Cell RNA Sequencing Identifies FIXER, a Conserved Profibrogenic Long Noncoding RNA. Circulation, 148(9), pp. 778-797. American Heart Association 10.1161/CIRCULATIONAHA.122.062601

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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. FIXER mechanistically associates with CBX4, an E3 SUMO (small ubiquitin-like modifier) protein ligase and a transcription factor, target CBX4 to the promoter of the transcription factor RUNX1 to regulate its expression and thereby the whole 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.

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