Resolving patient heterogeneity in critical illness requires multi-scale approaches.
Resolving patient heterogeneity in critical illness requires multi-scale approaches.
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DOI：
10.1016/j.ebiom.2022.103918
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发表时间：
2022-03
期刊：
影响因子：
11.1
通讯作者：
Scicluna BP
中科院分区：
文献类型：
--
作者：
Scicluna BP
环境暴露，包括微生物，有毒物质和疫苗，可以显着影响免疫细胞的功能状态。现在公认的是，细胞的身份和功能状态受到严格调控的时空基因表达程序。建立细胞类型同一性在很大程度上取决于许多转录因子的协调分布，所述转录因子结合至具有顺式调节元件的可接近的染色质区域，从而激活或抑制基因表达（图1A）。1因此，识别特定细胞类型基因组中可接近的顺式元件是深入了解健康和疾病的重要一步。考虑到可接近顺式调节元件通常对核酸酶或转座酶（无论是活性的还是静止的）超敏感，使用测序的转座酶可亲和染色质测定（ATAC-seq）2已广泛用于绘制染色质可接近性模式（图1 B）。为了克服复杂组织样品在解析细胞特异性事件中的局限性，最近开发了用于在单细胞水平上测量染色质可及性的方法（scATAC-seq）。从严重创伤和烧伤的危重患者中获得的血液白细胞的转录谱显示了与器官功能障碍程度和结果相关的基因表达的实质性改变。3将单细胞RNA测序应用于从创伤患者获得的外周血单核细胞（PBMC），揭示了髓样细胞（主要是单核细胞）中的基因表达模式显著地导致了稳态的偏离。4值得注意的是，关键转录因子的基因表达变化可能归因于髓系祖细胞库。这些创伤诱导的基因表达变化是否反映了染色质可及性模式是一个悬而未决的问题。在本期eBioMedicine中，Chen及其同事通过使用scATAC-seq在从创伤患者获得的PBMC中测试染色质可及性来解决这个问题。5正如预期的那样，基因表达改变在很大程度上伴随着开放的染色质构象，作者将其分层为与充分表征的炎症和免疫抑制基因集相关的“焦点”位点，或以基因表达变化为特征的“全局”位点，这些基因表达变化与免疫应答非特异性途径相协调，包括Polycomb靶点的去抑制，参与DNA修复和RNA加工的基因的抑制。随后在全血白细胞转录组的大型数据集中探索了这种“全局表观遗传特征”，以及创伤、严重烧伤3和败血症6、7队列的相关临床结局。使用基因过滤生物信息学策略，作者发现，首先，将“全局”表观遗传学改变（指定为EG亚型）与先前由同一组导出的炎症反应转录组学特征（称为SG亚型）相结合，比单独使用EG或SG亚型更好地解决了创伤引起的危重病中的患者异质性。此外，有趣的是，与“全局”表观遗传组相关的基因的较高表达与烧伤或脓毒症引起的危重病的不良结局相关。表观遗传组亚型的潜在预后价值独立于参与典型免疫反应途径的基因的转录变化，包括促炎、抗炎信号传导、抗原呈递和干扰素信号传导途径，这些途径与该小组先前研究中的转录组SG亚型相关，也定义了这些基因的转录水平。
Environmental exposures, including microbes, toxic substances, and vaccines, can significantly impact the functional state of immune cells. It is now accepted that cell identity and functional states are governed by tightly regulated spatiotemporal gene expression programs. Establishing cell type identity depends largely on the coordinated distribution of numerous transcription factors that bind to accessible chromatin regions harbouring cis-regulatory elements, thereby activate or repress gene expression (Figure 1 A). 1 Therefore, identifying the accessible cis-elements in the genome of specific celltypes is an essential step towards a deeper understanding of health and disease. Considering accessible cisregulatory elements are typically hypersensitive to nucleases or transposases (whether active or poised), the Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) 2 has been widely used to map chromatin accessibility patterns (Figure 1 B). To overcome the limitations of complex tissue samples in resolving cell specific events, methods were recently developed for measuring chromatin accessibility at the level of single cells (scATAC-seq). Transcriptional profiling of blood leukocytes obtained from critically ill patients due to severe trauma and burn injuries revealed substantial alterations in gene expression that were associated with extent of organ dysfunction and outcomes. 3 Applying single cell RNA-sequencing to peripheral blood mononuclear cells (PBMCs) obtained from trauma patients, revealed gene expression patterns in myeloid cells (mainly monocytes) contributed markedly to departure from steady state. 4 Notably, gene expression changes in key transcription factors could be attributed to the myeloid progenitor pool. Whether those trauma-induced gene expression changes reflected chromatin accessibility patterns was an open question. In this issue of eBioMedicine, Chen and colleagues addressed this question by testing chromatin accessibility using scATAC-seq in PBMCs obtained from trauma patients. 5 As expected, gene expression alterations were largely concomitant with open chromatin conformations, which the authors stratified as either “focal” loci, associated with well-characterized inflammatory and immune suppressive gene sets, or “global” loci characterized by gene expression changes attuned to pathways unspecific to the immune response, including de-repression of Polycomb targets, suppression of genes involved in DNA repair and RNA processing. This “global epigenetic signature” was subsequently explored in large datasets of whole-blood leukocyte transcriptomes and the associated clinical outcomes from trauma, severe burns, 3 and sepsis 6, 7 cohorts. Using a gene filtering bioinformatics strategy, the authors found that, firstly, combining the “global” epigenetic alterations (designated EG subtypes) with an inflammatory response transcriptomic signature (termed SG subtypes), which was previously derived by the same group, provided better resolution of patient heterogeneity in critical illness due to trauma than using either EG or SG subtypes in isolation. Moreover, and intriguingly, higher expression of genes associated with the “global” epigenetic group was associated with worse outcomes in critical illness due to burns or sepsis. The potential prognostic value of the epigenetic group subtypes was independent of transcriptional changes of genes involved in typical immune response pathways, including pro-, anti-inflammatory signalling, antigen presentation, and interferon signalling pathways, which were associated with transcriptomic SG subtypes in the group’s previous study, and also defined …
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影响因子：
81.5
作者：
Matthay, Michael A.;Zemans, Rachel L.;Calfee, Carolyn S.
通讯作者：
Calfee, Carolyn S.
DOI：
10.1084/jem.20111354
发表时间：
2011-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Xiao W;Mindrinos MN;Seok J;Cuschieri J;Cuenca AG;Gao H;Hayden DL;Hennessy L;Moore EE;Minei JP;Bankey PE;Johnson JL;Sperry J;Nathens AB;Billiar TR;West MA;Brownstein BH;Mason PH;Baker HV;Finnerty CC;Jeschke MG;López MC;Klein MB;Gamelli RL;Gibran NS;Arnoldo B;Xu W;Zhang Y;Calvano SE;McDonald-Smith GP;Schoenfeld DA;Storey JD;Cobb JP;Warren HS;Moldawer LL;Herndon DN;Lowry SF;Maier RV;Davis RW;Tompkins RG;Inflammation and Host Response to Injury Large-Scale Collaborative Research Program
通讯作者：
Inflammation and Host Response to Injury Large-Scale Collaborative Research Program
影响因子：
64.8
作者：
Shen, Yin;Yue, Feng;McCleary, David F.;Ye, Zhen;Edsall, Lee;Kuan, Samantha;Wagner, Ulrich;Dixon, Jesse;Lee, Leonard;Lobanenkov, Victor V.;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
76.2
作者：
Scicluna, Brendon P.;van Vught, Lonneke A.;van der Poll, Tom
通讯作者：
van der Poll, Tom
影响因子：
8.8
作者：
DeMerle KM;Angus DC;Baillie JK;Brant E;Calfee CS;Carcillo J;Chang CH;Dickson R;Evans I;Gordon AC;Kennedy J;Knight JC;Lindsell CJ;Liu V;Marshall JC;Randolph AG;Scicluna BP;Shankar-Hari M;Shapiro NI;Sweeney TE;Talisa VB;Tang B;Thompson BT;Tsalik EL;van der Poll T;van Vught LA;Wong HR;Yende S;Zhao H;Seymour CW
通讯作者：
Seymour CW