LncRNA Bigheart trans-activates gene expression in a feed forward mechanism that facilitates calcineurin-NFAT signaling in myocardial hypertrophy

Mangraviti, N.; Ruhle, F.; Kinet, V.; Hegenbarth, J.-C.; Dirkx, E.; Spano, G.; De Majo, F.; Peppas, P.; Martens, L.; Ghandi, S.; Colpaert, R.; Ruperez, C.; Olieslagers, S.; Falcao-Pires, I.; Calore, M.; Witten, A.; da Costa Martins, P.; Mayr, M.; Muller, O.; Stoll, M.; De Windt, L. J.

doi:10.1101/2023.12.11.571094

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bioRxiv · 10.1101/2023.12.11.571094

LncRNA Bigheart trans-activates gene expression in a feed forward mechanism that facilitates calcineurin-NFAT signaling in myocardial hypertrophy

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Abstract

Terminally differentiated cardiomyocytes exhibit hypertrophy as a default response to injury by translating biomechanical stress into a complex network of intracellular signaling events. The molecular intricacies how calcium-dependent signaling engage molecular circuits and epigenetic modifications to activate deleterious gene programs remain enigmatic. Here we report on the re-activation of the evolutionarily conserved lncRNA "Bigheart", which is repressed in the postnatal myocardium and quickly re-activated in a calcineurin-NFAT-dependent fashion in the diseased myocardium in man and mouse. In line, AAV9-mediated overexpression of lncRNA Bigheart in otherwise healthy primary cardiomyocytes or mouse hearts suffices to drive maladapative hypertrophy. Conversely, mice receiving a "Gapmer" antisense oligonucleotide designed to specifically silence endogenous lncRNA Bigheart display resistance to biomechanical stress-induced myocardial remodeling, indicating its requirement in left ventricular hypertrophy. Mechanistically, lncRNA Bigheart recruits the RNA binding proteins hnRNP-F1 and HMGB1 to modulate the local chromatin environment and trans-activate Bigheart target genes including Rcan1 to stimulate calcineurin-NFAT coupling. Our observations confirm that human heart failure arises from specific susceptibilities in gene regulatory circuits that are amenable for therapeutic intervention using RNA-based therapeutics.

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Mangraviti, N., Ruhle, F., Kinet, V., Hegenbarth, J.-C., Dirkx, E., Spano, G., De Majo, F., Peppas, P., Martens, L., Ghandi, S., Colpaert, R., Ruperez, C., Olieslagers, S., Falcao-Pires, I., Calore, M., Witten, A., da Costa Martins, P., Mayr, M., Muller, O., Stoll, M., De Windt, L. J.. 2023-12-12. LncRNA Bigheart trans-activates gene expression in a feed forward mechanism that facilitates calcineurin-NFAT signaling in myocardial hypertrophy. https://doi.org/10.1101/2023.12.11.571094

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