Longitudinal Study of DNA Methylation and Epigenetic Clocks Prior to and Following Test-Confirmed COVID-19 and mRNA Vaccination.
Longitudinal Study of DNA Methylation and Epigenetic Clocks Prior to and Following Test-Confirmed COVID-19 and mRNA Vaccination.
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DOI：
10.3389/fgene.2022.819749
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发表时间：
2022
影响因子：
3.7
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中科院分区：
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在SARS-CoV-2感染期间，宿主表观遗传景观迅速发生变化，有证据表明，严重的COVID-19与表观基因组的持久疤痕有关。具体而言，免疫细胞中异常的DNA甲基化变化和血液中表观遗传时钟的改变与严重的COVID-19有关。然而，尚未对测试确认的非住院COVID-19之前和之后健康个体血液中的DNA甲基化状态和表观遗传时钟进行纵向评估。此外，mRNA - COVID-19疫苗对宿主表观基因组的影响仍未得到充分研究。在这里，我们首先在8.35周的中位时间框架内检查了21名参与者在测试确认的COVID-19诊断之前和之后血液中的DNA甲基化状态；756个CpGs在COVID-19诊断后被鉴定为差异甲基化，经FDR调整的p值< 0.05。这些CpGs富集于基因体以及参与代谢途径的基因的南北陆架区域。综合分析显示，转录SARS-CoV-2感染数据集中鉴定的基因存在重叠。在50岁以上的人群中，基于主成分的表观遗传时钟估计的表型年龄和GrimAge在感染后平均增加了2.1年和0.84年。相比之下，50岁以下人群感染后PCPhenoAge平均下降2.06年。这种观察到的表观遗传时钟在COVID-19后的差异与CD4+ T细胞、B细胞、粒细胞、浆母细胞、耗竭T细胞和naïve T细胞的年龄和免疫细胞类型组成变化有关。在辉瑞和Moderna基于mrna的COVID-19疫苗接种前后对36名参与者进行的补充性纵向表观遗传钟分析显示，对于接种Moderna的50岁以上人群，疫苗接种显着降低了基于主成分的Horvath表观遗传钟估计，平均减少了3.91年。表观遗传时钟估计值的降低与接种前后B细胞和浆母细胞的实足年龄和免疫细胞类型组成变化显著相关。这些发现表明表观遗传时钟作为COVID-19疫苗反应的生物标志物的潜在效用。未来的研究将需要揭示与COVID-19暴露和mRNA疫苗接种相关的表观遗传年龄短期变化的重要性和持久性。
The host epigenetic landscape rapidly changes during SARS-CoV-2 infection, and evidence suggest that severe COVID-19 is associated with durable scars to the epigenome. Specifically, aberrant DNA methylation changes in immune cells and alterations to epigenetic clocks in blood relate to severe COVID-19. However, a longitudinal assessment of DNA methylation states and epigenetic clocks in blood from healthy individuals prior to and following test-confirmed non-hospitalized COVID-19 has not been performed. Moreover, the impact of mRNA COVID-19 vaccines upon the host epigenome remains understudied. Here, we first examined DNA methylation states in the blood of 21 participants prior to and following test-confirmed COVID-19 diagnosis at a median time frame of 8.35 weeks; 756 CpGs were identified as differentially methylated following COVID-19 diagnosis in blood at an FDR adjusted p-value < 0.05. These CpGs were enriched in the gene body, and the northern and southern shelf regions of genes involved in metabolic pathways. Integrative analysis revealed overlap among genes identified in transcriptional SARS-CoV-2 infection datasets. Principal component-based epigenetic clock estimates of PhenoAge and GrimAge significantly increased in people over 50 following infection by an average of 2.1 and 0.84 years. In contrast, PCPhenoAge significantly decreased in people fewer than 50 following infection by an average of 2.06 years. This observed divergence in epigenetic clocks following COVID-19 was related to age and immune cell-type compositional changes in CD4+ T cells, B cells, granulocytes, plasmablasts, exhausted T cells, and naïve T cells. Complementary longitudinal epigenetic clock analyses of 36 participants prior to and following Pfizer and Moderna mRNA-based COVID-19 vaccination revealed that vaccination significantly reduced principal component-based Horvath epigenetic clock estimates in people over 50 by an average of 3.91 years for those who received Moderna. This reduction in epigenetic clock estimates was significantly related to chronological age and immune cell-type compositional changes in B cells and plasmablasts pre- and post-vaccination. These findings suggest the potential utility of epigenetic clocks as a biomarker of COVID-19 vaccine responses. Future research will need to unravel the significance and durability of short-term changes in epigenetic age related to COVID-19 exposure and mRNA vaccination.