Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients.
Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients.
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DOI：
10.1016/j.xcrm.2023.100935
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发表时间：
2023-02-21
影响因子：
14.3
通讯作者：
Coufal, Nicole G.
中科院分区：
文献类型：
--
作者：
Lam, Michael Tun Yin;Duttke, Sascha H.;Odish, Mazen F.;Le, Hiep D.;Hansen, Emily A.;Nguyen, Celina T.;Trescott, Samantha;Kim, Roy;Deota, Shaunak;Chang, Max W.;Patel, Arjun;Hepokoski, Mark;Alotaibi, Mona;Rolfsen, Mark;Perofsky, Katherine;Warden, Anna S.;Foley, Jennifer;Ramirez, Sydney I.;Dan, Jennifer M.;Abbott, Robert K.;Crotty, Shane;Alexander, Laura E. Crotty;Malhotra, Atul;Panda, Satchidananda;Benner, Christopher W.;Coufal, Nicole G.
调节2019冠状病毒病（COVID-19）免疫反应的转录因子程序尚未完全了解。通过加帽的小RNA测序（csRNA-seq）捕获来自顺式调节元件如增强子和启动子的活性转录起始，与通过常规RNA-seq捕获稳态转录物相反，允许无偏地鉴定潜在的转录因子活性和调节途径。在这里，我们分析了重症COVID-19患者的转录起始，确定了与临床肺损伤和疾病严重程度相关的转录因子基序。无偏聚类揭示了不同的子集的顺式调控元件，描绘了细胞类型，通路特异性，和组合转录因子的活性。我们发现了调控网络的关键作用的证据，表明来自骨髓细胞群体的STAT/BCL 6和E2 F/MYB调控程序在疾病结局较差的患者中被激活，并与COVID-19易感性遗传变异相关。更广泛地说，我们展示了如何捕捉急性，疾病介导的转录起始变化可以提供深入了解潜在的分子机制和分层患者疾病的严重程度。免疫顺式调节活性在COVID-19 ICU患者的病程中是动态的特异性顺式调节簇的活性跟踪临床肺损伤独特的转录因子基序在顺式调节簇STAT/BCL 6、T1 ISRE/STAT和E2 F/MYB中富集活动与不良结局相关了解非编码调节DNA在重症疾病中的功能尚未得到充分研究。Lam等人将调控DNA的动态活性与COVID-19 ICU患者的临床进展相结合。对这些调控元件中的DNA结合序列的分析揭示了转录因子活性作为疾病严重程度指标的作用。
Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes and associated with COVID-19 susceptibility genetic variants. More broadly, we demonstrate how capturing acute, disease-mediated changes in transcription initiation can provide insight into the underlying molecular mechanisms and stratify patient disease severity. Immune cis-regulatory activities are dynamic in COVID-19 ICU patients’ courses The activity of specific cis-regulatory clusters tracks clinical lung injury Distinct transcription factor motifs are enriched in cis-regulatory clusters STAT/BCL6, T1ISRE/STAT, and E2F/MYB activities are associated with poor outcomes Understanding how non-coding regulatory DNA functions in critical illnesses is understudied. Lam et al. integrate the dynamic activities of regulatory DNA with the clinical progression of COVID-19 ICU patients. Analysis of DNA binding sequences in these regulatory elements reveals the roles of transcription factor activities as indicators of disease severity.
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DOI：
10.1186/s13054-015-0981-y
发表时间：
2015-06-16
期刊：
Critical care (London, England)
影响因子：
--
作者：
Acosta-Herrera M;Pino-Yanes M;Blanco J;Ballesteros JC;Ambrós A;Corrales A;Gandía F;Subirá C;Domínguez D;Baluja A;Añón JM;Adalia R;Pérez-Méndez L;Flores C;Villar J;GRECIA and GEN-SEP networks
通讯作者：
GRECIA and GEN-SEP networks
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
7
作者：
Duttke, Sascha H.;Chang, Max W.;Benner, Christopher
通讯作者：
Benner, Christopher
DOI：
10.4049/jimmunol.1600043
发表时间：
2016-10-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gomez JC;Dang H;Martin JR;Doerschuk CM
通讯作者：
Doerschuk CM
影响因子：
76.2
作者：
Calfee, Carolyn S.;Delucchi, Kevin;Parsons, Polly E.;Thompson, B. Taylor;Ware, Lorraine B.;Matthay, Michael A.
通讯作者：
Matthay, Michael A.