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<p>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 <i>HSCHARME</i> 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 <i>HSCHARME</i> in hiPSC-derived cardiomyocytes, we report that the locus produces the major <i>pCHARME</i> isoform that associates with SC35-containing speckles and interacts with the splicing regulator PTBP1. Consistently, the functional inactivation of <i>pCHARME</i> 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 <i>pCHARME</i> in hypertrophic and dilated hearts. We also find that <i>HSCHARME</i> dosage can modulate the expression of a subset of disease-associated targets. Our findings provide mechanistic insights into the role of <i>pCHARME</i> in cardiac cells with potential implications for disease.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月23日

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  • Giulia Buonaiuto,
  • Fabio Desideri,
  • Adriano Setti,
  • Alessandro Palma,
  • Angelo D’Angelo,
  • Giulio Storari,
  • Tiziana Santini,
  • Pietro Laneve,
  • Daniela Trisciuoglio,
  • Monica Ballarino

摘要

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.