LncRNA HSCHARME is altered in human cardiomyopathies and promotes stem cell-derived cardiomyogenesis via splicing regulation

Giulia Buonaiuto, Fabio Desideri, Adriano Setti, Alessandro Palma, Angelo D’Angelo, Giulio Storari, Tiziana Santini, Pietro Laneve, Daniela Trisciuoglio and Monica Ballarino ()
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Giulia Buonaiuto: Sapienza University of Rome
Fabio Desideri: Center for Life Nano- & Neuro-Science of Istituto Italiano di Tecnologia (IIT)
Adriano Setti: Sapienza University of Rome
Alessandro Palma: Sapienza University of Rome
Angelo D’Angelo: Sapienza University of Rome
Giulio Storari: Sapienza University of Rome
Tiziana Santini: Sapienza University of Rome
Pietro Laneve: Sapienza University of Rome
Daniela Trisciuoglio: Institute of Molecular Biology and Pathology (IBPM-CNR)
Monica Ballarino: Sapienza University of Rome

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract A growing body of evidence suggests that tissue-specific lncRNAs play pivotal roles in the heart. Here, we exploit the synteny between the mouse and human genomes to identify the human lncRNA HSCHARME and combine single-cell transcriptomics, CAGE-seq data, RNA-FISH imaging and CRISPR/Cas9 genome editing to document its role in cardiomyogenesis. By investigating the mechanism of action of HSCHARME in hiPSC-derived cardiomyocytes, we report that the locus produces the major pCHARME isoform that associates with SC35-containing speckles and interacts with the splicing regulator PTBP1. Consistently, the functional inactivation of pCHARME influences the splicing of cardiac-specific pre-mRNAs and impacts their expression, which reflects a decline in cardiomyocyte differentiation and physiology. In line with a possible association with disease, large-scale analysis of the lncRNA expression across cardiomyopathy patients reveals increased levels of pCHARME in hypertrophic and dilated hearts. We also find that HSCHARME dosage can modulate the expression of a subset of disease-associated targets. Our findings provide mechanistic insights into the role of pCHARME in cardiac cells with potential implications for disease.

Date: 2025
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DOI: 10.1038/s41467-025-62754-2

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