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

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 (Human Syntenic CHARME) and combined single-cell transcriptomics, CAGE-seq data, RNA-FISH imaging and CRISPR-Cas9 genome editing to document its role in cardiomyogenesis. We found that the functional inactivation of HSCHARME in hiPSC-derived cardiomyocytes (CM) impairs the expression of calcium handling and contraction genes, with a consequent decline of CM maturation and contractile functions. Consistent with a possible association with disease, large-scale analysis of the lncRNA expression across cardiomyopathy patients revealed increased levels of HSCHARME in hypertrophic (HCM) and dilated (DCM) hearts and identified a subset of diseased-associated targets whose expression can be modulated through HSCHARME dosage. Overall, our data unlock the potential of HSCHARME as a novel non-coding regulator of CM physiology and open new possibilities for the therapeutic application of the lncRNA in disease.