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

项目概述：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。重症患者表现出 改变循环血液DNA甲基化谱。我们最近报道了一个大规模的甲基化分析 COVID-19与临床结果相关，这表明基因控制的表观遗传调节 疾病严重程度。最近的证据表明，许多幸存的COVID-19患者 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）。目前尚不清楚是否引起了快速甲基化调节 急性疾病在SARS-CoV-2消退后持续存在。这种持续性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，鉴于我们最近发现， 在急性疾病期间发生的持续差异甲基化在出院后一年，我们 假设COVID-19感染导致持续的DNA甲基化异常， 解决与COVID-19后临床特征相关的急性疾病。在本申请中，我们 计划进行循环白细胞的全基因组DNA甲基化和RNA测序，以建立亚组DNA甲基化和RNA测序。 PASC的表型，预测未来PASC在急性COVID-19中的发展，并确定 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.