Fei-Man Hsu, Rashmi P Mohanty, Liudmilla Rubbi, Michael Thompson, Harry Pickering, Elaine F Reed, John R Greenland, Joanna M Schaenman, Matteo Pellegrini
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引用次数: 0
摘要
巨细胞病毒(CMV)在实体器官移植(SOT)受者中的感染和再激活会增加病毒血症、移植失败和死亡的风险。对 CMV 血清状态的临床研究表明,供体阳性、受体阴性(D+/R-)的患者比 D-/R- 患者感染病毒的风险更大。大多数患者为 R+,血清学风险居中。为了确定 CMV 感染的长期影响并评估病毒血症风险,我们试图测量 CMV 对受体免疫表观基因组的影响。具体来说,我们对肺移植或肾移植前的 156 人进行了 DNA 甲基化分析。我们发现,CMV 阳性的 SOT 受体的甲基组在与神经发育和多聚核糖体(PcG)蛋白结合相关的位点上甲基化过度,而在对淋巴细胞成熟至关重要的区域甲基化不足。此外,我们还开发了一种基于机器学习的模型,在校正细胞类型组成和血统后预测受体的 CMV 血清状态。在基线时测量的R+个体的CMV外显子可对肺移植队列中的病毒血症风险进行精确分层,CMV外显子与血清状态一起可作为识别高病毒血症风险的R+患者的潜在生物标志物。
An epigenetic human cytomegalovirus infection score predicts viremia risk in seropositive lung transplant recipients.
Cytomegalovirus (CMV) infection and reactivation in solid organ transplant (SOT) recipients increases the risk of viremia, graft failure and death. Clinical studies of CMV serostatus indicate that donor positive recipient negative (D+/R-) patients have greater viremia risk than D-/R-. The majority of patients are R+ having intermediate serologic risk. To characterize the long-term impact of CMV infection and assess viremia risk, we sought to measure the effects of CMV on the recipient immune epigenome. Specifically, we profiled DNA methylation in 156 individuals before lung or kidney transplant. We found that the methylome of CMV positive SOT recipients is hyper-methylated at loci associated with neural development and Polycomb group (PcG) protein binding, and hypo-methylated at regions critical for the maturation of lymphocytes. In addition, we developed a machine learning-based model to predict the recipient CMV serostatus after correcting for cell type composition and ancestry. This CMV episcore measured at baseline in R+ individual stratifies viremia risk accurately in the lung transplant cohort, and along with serostatus the CMV episcore could be a potential biomarker for identifying R+ patients at high viremia risk.
期刊介绍:
Epigenetics publishes peer-reviewed original research and review articles that provide an unprecedented forum where epigenetic mechanisms and their role in diverse biological processes can be revealed, shared, and discussed.
Epigenetics research studies heritable changes in gene expression caused by mechanisms others than the modification of the DNA sequence. Epigenetics therefore plays critical roles in a variety of biological systems, diseases, and disciplines. Topics of interest include (but are not limited to):
DNA methylation
Nucleosome positioning and modification
Gene silencing
Imprinting
Nuclear reprogramming
Chromatin remodeling
Non-coding RNA
Non-histone chromosomal elements
Dosage compensation
Nuclear organization
Epigenetic therapy and diagnostics
Nutrition and environmental epigenetics
Cancer epigenetics
Neuroepigenetics