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。危重病人表现 改变循环血液 DNA 甲基化谱。我们最近报道了大规模甲基化组分析 COVID-19 与临床结果的相关性，这表明控制基因的表观遗传调控 疾病的严重程度。最近的证据表明，许多幸存的 COVID-19 患者会出现长期症状 NIH-NHLBI 最近发起了一项倡议，旨在阐明急性后疾病的本质 SARS-CoV-2 感染 (PASC) 的后遗症。目前尚不清楚甲基化组的快速调控是否由 SARS-CoV-2 消退后，急性疾病仍持续存在。这种坚持可能会导致长期后遗症 与这种情况有关。因为DNA甲基化是一种相对稳定的DNA化学修饰， 可能会影响长期的基因表达谱，并且考虑到我们最近发现多个区域 出院一年后在急性疾病期间持续存在差异甲基化，我们 假设 COVID-19 感染导致持久的 DNA 甲基化异常，这种异常在感染后仍然存在 与 COVID-19 后临床特征相关的急性疾病的解决。在这个应用程序中，我们 计划对循环白细胞进行全基因组DNA甲基化和RNA测序，以建立子 PASC 的表型，预测急性 COVID-19 中 PASC 的未来发展，并确定哪些循环 白细胞谱系有助于持久的甲基化。

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.