Abstract
Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.
Highlights
We describe the identification of the Long non-coding RNAs (lncRNAs) Sarrah, which is repressed during aging, and show that silencing Sarrah induces apoptosis and delays cardiac contractile force development in human engineered heart tissue (EHT)
We identified 29,150 transcripts, of which 5439 were annotated as lncRNAs that are expressed in the cardiomyocyte fraction (Supplementary Fig. 1B)
To assess whether any of the identified lncRNAs regulates apoptosis, we employed an siRNA-based screening approach to reduce expression levels of all 76 lncRNAs identified above in combination with a caspase-3/7 activity-based apoptosis assay (Fig. 1a). This assay showed that the lncRNA with the largest effect on apoptosis in HL-1 cardiomyocytes was a transcript annotated as ENSMUST0000014000313. As this was the most potent effect we observed, we further focused on this lncRNA and named it Sarrah (SCOT1-antisense RNA regulated during aging in the heart) since it is transcribed from the antisense locus of the OXCT1 gene encoding the enzyme Sarrah locus OXCT1 (SCOT1)
Summary
Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Involved in epigenetic control, Fendrr regulates heart development by modifying PRC2 occupancy at target genes[8,9] Mhrt, another cardioprotective lncRNA, sequesters Brg[1] from chromatin targets to prevent hypertrophic gene expression[10]. We describe the identification of the lncRNA Sarrah (short for SCOT1-antisense RNA regulated during aging in the heart), which is repressed during aging, and show that silencing Sarrah induces apoptosis and delays cardiac contractile force development in human engineered heart tissue (EHT). Sarrah forms a DNA-DNA-RNA triplex with promoters of cardiac survival genes to recruit CRIP2 and activate gene expression. One of these target genes that confers its antiapoptotic function is NRF2. We show that Sarrah can be used to therapeutically augment cardiac function after acute myocardial infarction in mice
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