Pant, P.; Sivakumar, P.; Nanda, D.; Ram, S.; Dhandapany, P. S.; Thum, T.; Regalla, K.

Long non-coding RNAs (lncRNAs) play a crucial role in fine-tuning the gene expression. In the present study, we identified that the lncRNA NEAT1 is upregulated in failing murine hearts and in human hypertrophic cardiomyopathies. Further investigations demonstrated that NEAT1 expression is regulated by calcium dependent NFAT (nuclear factor of activated T cells). Overexpression of NEAT1 led to increased cardiomyocyte size and elevated expression of cardiac stress markers while its depletion had the opposite effect. Through transcriptomic analysis in NEAT1-KO cells, we demonstrated the cis-regulatory role of NEAT1, wherein it maintains the transcription of neighboring genes by interacting with the coactivator p300. Additionally, NEAT1 depletion resulted in decreased expression of GRK2 (G protein-coupled receptor kinase 2), a key player in the development of cardiac hypertrophy, suggesting that NEAT1 contributes to the development of cardiac hypertrophy by regulating GRK2 expression. Consistent with this, Neat1-/- mice are resistant to beta-adrenergic stimulation. Overall, our study provides enough evidence that NEAT1 is a calcium-regulated, pro-hypertrophic lncRNA that exerts significant control over the transcriptional landscape of cardiomyocytes during heart failure.