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.
摘要:
长链非编码RNA(lncRNAs)在心脏病中异常表达,但它们在心肌肥厚中的作用尚不清楚。在这里,我们试图鉴定特定的lncRNA并探索lncRNA功能的潜在机制。我们的结果表明,通过使用染色质免疫沉淀测序(ChIP-Seq),lncRNASnhg7是心脏肥大中的超增强子驱动基因。我们接下来发现,lncRNASnhg7通过与T-box转录因子5(Tbx5)相互作用诱导铁凋亡,心脏转录因子.此外,Tbx5与谷氨酰胺酶2(GLS2)的启动子结合,并在心肌肥大中调节心肌细胞的铁凋亡活性。重要的是,末端外结构域抑制剂JQ1可以抑制心脏肥大中的超增强子。抑制lncRNASnhg7可以阻断Tbx5、GLS2的表达和心肌细胞铁凋亡水平。此外,我们验证了Nkx2-5作为核心转录因子,直接结合自身的超级增强子和lncRNASnhg7,增加它们的激活。总的来说,我们首次将lncRNASnhg7鉴定为心脏肥大中的新型功能性lncRNA,可能通过铁蛋白调节心脏肥大。机械上,lncRNASnhg7可以转录调节心肌细胞Tbx5/GLS2/铁凋亡。