Super-enhancer-driven lncRNA Snhg7 aggravates cardiac hypertrophy via Tbx5/GLS2/ferroptosis axis

Abstract

Long non-coding RNAs (lncRNAs) are expressed aberrantly in cardiac disease, but their roles in cardiac hypertrophy are still unknown. Here we sought to identify a specific lncRNA and explore the mechanisms underlying lncRNA functions. Our results revealed that lncRNA Snhg7 was a super-enhancer-driven gene in cardiac hypertrophy by using chromatin immunoprecipitation sequencing (ChIP-seq). We next found that lncRNA Snhg7 induced ferroptosis by interacting with T-box transcription factor 5 (Tbx5), a cardiac transcription factor. Moreover, Tbx5 bound to the promoter of glutaminase 2 (GLS2) and regulated cardiomyocyte ferroptosis activity in cardiac hypertrophy. Importantly, extra-terminal domain inhibitor JQ1 could suppress super-enhancers in cardiac hypertrophy. Inhibition of lncRNA Snhg7 could block the expressions of Tbx5, GLS2 and levels of ferroptosis in cardiomyocytes. Furthermore, we verified that Nkx2-5 as a core transcription factor, directly bound the super-enhancer of itself and lncRNA Snhg7, increasing both of their activation. Collectively, we are the first to identify lncRNA Snhg7 as a novel functional lncRNA in cardiac hypertrophy, might regulate cardiac hypertrophy via ferroptosis. Mechanistically, lncRNA Snhg7 could transcriptionally regulate Tbx5/GLS2/ferroptosis in cardiomyocytes.

Keywords: Cardiac hypertrophy; Ferroptosis; LncRNA Snhg7; Nkx2-5; Super-enhancers; Tbx5.