An aberrant resurrection of endogenous retrovirus prompts acute myocarditis and heart failure

The abberant resurgence of which have been recently found to link to some critical pathologies. To evaluate the occurrence and role of ERV resurrgenece in heart and heart failure (HF), we conducted heart total RNA-seq analysis from mice ischemia-reperfusion (I/R) heart failure models and found that ERVs were activated which is similar in various cross-species models of heart failure. To explore the mechanism of ERVs resurgence we profiled trimethylation at lysine 9 of histone H3 (H3K9me3) ChIP- and MeRIP-seq of cardiomyocytes specific TRIM28 knockout mice heart. The deprivation of TRIM28 in the mouse myocardium attenuated the epigenetic surveillance of H3K9me3 and N6-methyladenosine (m6A), and revived the ERVs, which consequently activated the intracellular antiviral innate immune pathways of TLR7-9 and NF-kappaB and lead to the myocarditis and acute heart failure. For total RNA-seq of I/R mice, ischemia was created by temporarily ligating the left anterior descending coronary artery for 45 min and reperfusion for 24h. Hearts were collected and then extracted and total RNA sequencing was performed. For total RNA-seq, H3K9me3 ChIP-seq and MeRIP-seq of TRIM28 iCKO mice, the genomic deletion of TRIM28 was introduced via an intraperitoneal administration of 25mg/kg tamoxifen dissolved in corn oil for a consecutive five days. After 1week, hearts were extracted then total RNA, ChIP and MeRIP sequencing was performed.

近期研究发现，异常重现的内源性逆转录病毒（ERV）与多种重症病理过程存在密切关联。
为评估ERV重现现象在心脏及心力衰竭（HF）中的发生情况与作用机制，我们针对小鼠缺血再灌注（I/R）心力衰竭模型开展了心脏总RNA测序（RNA-seq）分析，结果发现ERV被激活，且该激活特征在多种跨物种心力衰竭模型中均存在。
为探究ERV重现的分子机制，我们对心肌细胞特异性TRIM28敲除小鼠的心脏进行了组蛋白H3第9位赖氨酸三甲基化（H3K9me3）染色质免疫共沉淀测序（ChIP-seq）及甲基化RNA免疫沉淀测序（MeRIP-seq）检测。
小鼠心肌组织中TRIM28的缺失会削弱H3K9me3与N6-甲基腺嘌呤（m6A）的表观遗传监控功能，进而激活ERV，最终启动细胞内抗病毒天然免疫通路——包括Toll样受体7-9（TLR7-9）与核因子κB（NF-κB）通路，最终引发心肌炎与急性心力衰竭。
针对I/R小鼠的总RNA测序实验：通过暂时性结扎左前降支冠状动脉45分钟、再灌注24小时构建缺血模型，收集心脏组织并提取总RNA，随后完成总RNA测序。
针对TRIM28诱导型条件性敲除（iCKO）小鼠的总RNA测序、H3K9me3 ChIP-seq及MeRIP-seq实验：通过腹腔注射溶于玉米油的他莫昔芬（剂量为25mg/kg），连续给药5天以诱导TRIM28的基因组缺失；给药1周后收集心脏组织，分别提取总RNA并开展测序，同时进行ChIP与MeRIP测序。