独立预后价值的全局表观遗传改变：对创伤患者循环白细胞单细胞 ATAC-seq 的分析，随后在三种危重病病因的全血白细胞转录组中进行验证。

The independent prognostic value of global epigenetic alterations: An analysis of single-cell ATAC-seq of circulating leukocytes from trauma patients followed by validation in whole blood leukocyte transcriptomes across three etiologies of critical illness.

机构信息

Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; Cellular and Molecular Pathology Program, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.

Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.

出版信息

EBioMedicine. 2022 Feb;76:103860. doi: 10.1016/j.ebiom.2022.103860. Epub 2022 Feb 3.

DOI:10.1016/j.ebiom.2022.103860

PMID:35124428

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8822299/

Abstract

BACKGROUND

While bulk and single cell transcriptomic patterns in circulating leukocytes from trauma patients have been reported, how these relate to changes in open chromatin patterns remain unstudied. Here, we investigated whether single-cell ATAC-seq would provide further resolution of transcriptomic patterns that align with patient outcomes.

METHODS

We performed scATAC-seq on peripheral blood mononuclear cells from four trauma patients at <4 h, 24 h, 72 h post-injury and four matched healthy controls, and extracted the features associated with the global epigenetic alterations. Three large-scale bulk transcriptomic datasets from trauma, burn and sepsis patients were used to validate the scATAC-seq derived signature, explore patient epigenetic heterogeneity (Epigenetic Groups: EG_hi vs. EG_lo), and associate patterns with clinical outcomes in critical illness.

FINDINGS

Patient subsets with gene expression patterns in blood leukocytes representative of a high global epigenetic signature (EG_hi) had worse outcomes across three etiologies of critical illness. EG_hi designation contributed independent of the known immune leukocyte transcriptomic responses to patient prognosis (Trauma: HR=0.62 [95% CI: 0.43-0.89, event set as recovery], p=0.01, n=167; Burns: HR=4.35 [95% CI: 0.816-23.2, event set as death], p=0.085, n=121; Sepsis: HR=1.60 [95% CI: 1.10-2.33, event set as death], p=0.013, n=479; Cox proportional hazards regression).

INTERPRETATION

The inclusion of gene expression patterns that associate with global epigenetic changes in circulating leukocytes improves the resolution of transcriptome-based patient classification in acute critical illnesses. Early detection of both the global epigenetic signature and the known immune transcriptomic patterns associates with the worse prognosis in trauma, burns and sepsis.

FUNDING

This project was supported by an R35 grant from National Institutes of Health: 1R35GM127027-01 (T.B.).

摘要

背景

虽然已经报道了创伤患者循环白细胞的整体和单细胞转录组模式，但这些与开放染色质模式的变化有何关联仍未得到研究。在这里，我们研究了单细胞 ATAC-seq 是否会提供与患者结局一致的转录组模式的进一步解析。

方法

我们对 4 名创伤患者伤后<4h、24h、72h 和 4 名匹配的健康对照者的外周血单核细胞进行 scATAC-seq 检测，并提取与整体表观遗传改变相关的特征。我们使用 3 个来自创伤、烧伤和脓毒症患者的大型批量转录组数据集来验证 scATAC-seq 衍生的特征，探索患者表观遗传异质性（表观遗传组：EG_hi 与 EG_lo），并将模式与危重病患者的临床结局相关联。

发现

在血液白细胞中具有高全局表观遗传特征（EG_hi）代表性基因表达模式的患者亚组在三种危重病病因中均有更差的结局。EG_hi 的指定有助于独立于已知的免疫白细胞转录组反应来预测患者预后（创伤：HR=0.62 [95%CI：0.43-0.89，事件集为恢复]，p=0.01，n=167；烧伤：HR=4.35 [95%CI：0.816-23.2，事件集为死亡]，p=0.085，n=121；脓毒症：HR=1.60 [95%CI：1.10-2.33，事件集为死亡]，p=0.013，n=479；Cox 比例风险回归）。