Blood DNA Methylation Biomarkers of Post AcuteSequelae of SARS CoV 2 Infection (PASC)

项目摘要：DNA 5‘-C-磷酸-G-3’(CpG)甲基化是一种共价表观遗传修饰， 调节基因表达，对年龄和环境因素高度敏感。危重病人展示 循环血液DNA甲基化谱改变。我们最近报道了一项大规模的甲基组分析 新冠肺炎与临床预后的关系，这表明控制基因的表观遗传调控 疾病的严重性。最近的证据表明，许多存活的新冠肺炎患者会发展成长期的 功能障碍和NIH-NHLBI最近发起了一项倡议，以阐明急性后 SARS-CoV-2感染后遗症(PASC)。目前尚不清楚甲基组的快速调控是否由 SARS-CoV-2病毒解决后，急性疾病仍然存在。这种坚持可能会为长期的后遗症奠定基础 与此情况相关的。因为DNA甲基化是一种相对稳定的DNA化学修饰 可能会影响长期基因表达谱，鉴于我们最近发现多个区域 在急性疾病期间发生的疾病在出院一年后持续差异甲基化，我们 假设新冠肺炎感染导致持久的DNA甲基化异常，这些异常在 急性疾病的解决与新冠肺炎后的临床概况相关。在此应用程序中，我们 计划对循环中的白细胞进行全基因组DNA甲基化和RNA测序，以建立亚群 PASC的表型，预测急性新冠肺炎患者PASC的未来发展，并确定哪些循环 白细胞谱系对这种持久的甲基组有贡献。

Project Summary: DNA 5'-C-phosphate-G-3' (CpG) methylation is a covalent epigenetic modification that regulates gene expression and is highly sensitive to age and environmental factors. Critically ill patients exhibit altered circulating blood DNA methylation profiles. We have recently reported a large scale methylome analysis of COVID-19 in association with clinical outcomes, which suggests an epigenetic regulation of genes controlling disease severity. Recent evidence indicates that many surviving COVID-19 patients develop long term dysfunctions and the NIH-NHLBI has recently launched an initiative to elucidate the nature of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). It is currently unknown if the rapid methylome regulation evoked by acute illness persist after SARS-CoV-2 resolution. Such persistence could underpin long term sequela associated with this condition. Because DNA methylation is a relatively stable DNA chemical modification that could influence long-term gene expression profiles and given that we recently found that multiple regions developed during acute illness persist differentially methylated one year after hospital discharge, we hypothesize that COVID-19 infection leads to enduring DNA methylation abnormalities that remain after resolution of acute illness in association with the post-COVID-19 clinical profile. In this application, we plan to conduct whole genome DNA methylation and RNA sequencing of circulating leucocytes to establish sub phenotypes of PASC, predict future PASC development in the acute COVID-19, and determine which circulating leucocyte lineage contributes to that enduring methylome.