Long noncoding RNA HSCHARME promotes the maturation of stem cells-derived cardiomyocytes by controlling gene regulatory networks altered in human cardiomyopathies

ABSTRACT A growing body of evidence suggests that tissue-specific long noncoding RNAs (lncRNA) play pivotal roles in the heart. Here, we exploited the synteny between the mouse and human genomes to identify the novel lncRNA HSCHARME ( H uman S yntenic CHARME ) and combined 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 found 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 parallels 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 revealed increased levels of pCHARME in hypertrophic (HCM) and dilated (DCM) hearts and identified a subset of disease-associated targets whose expression can be modulated through HSCHARME dosage. By unlocking mechanistic insights into the role of pCHARME in cardiac cells, our data identify a novel non-coding regulator of cardiomyocyte function with potential implications in disease.