@article{68823b26a31b41fe9e343d22b9d630dd,
title = "Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients",
abstract = "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.",
keywords = "active cistrome, acute respiratory distress syndrome, biomarkers, COVID-19, critical care, disease stratification, endotyping, enhancer RNA, transcription factor activity, transcriptional regulation",
author = "Lam, {Michael Tun Yin} and Duttke, {Sascha H.} and Odish, {Mazen F.} and Le, {Hiep D.} and Hansen, {Emily A.} and Nguyen, {Celina T.} and Samantha Trescott and Roy Kim and Shaunak Deota and Chang, {Max W.} and Arjun Patel and Mark Hepokoski and Mona Alotaibi and Mark Rolfsen and Katherine Perofsky and Warden, {Anna S.} and Jennifer Foley and Ramirez, {Sydney I.} and Dan, {Jennifer M.} and Abbott, {Robert K.} and Shane Crotty and {Crotty Alexander}, {Laura E.} and Atul Malhotra and Satchidananda Panda and Benner, {Christopher W.} and Coufal, {Nicole G.}",
note = "Funding Information: We are grateful to patients and their families for participation. We also thank the nurses in the UC San Diego-affiliated Medical Center ICU and the step-down unit for assistance. We thank Dr. Christopher K. Glass and Dr. Sven Heinz for advice. This work was supported by the NGS Core Facility of the Salk Institute with funding from NIH- NCI CCSG: P30 014195, the Chapman Foundation , and the Helmsley Charitable Trust . M.T.Y.L. is supported by the Academic Sleep Pulmonary Integrated Research/Clinical Fellowship through the American Thoracic Society , NIH ( 5T32HL134632-04 ), and Veterans Affair (1IK2BX005908). M.F.O. is supported by the NIH /National Institute of General Medical Science ( T32GM121318 ). R.K.A. is funded by NIH K99/R00 AI145762 . S.C. is funded by NIH/Cooperative Centers on Human Immunology (U19AI142742). S.H.D. is supported by NIH ( R00 GM135515 ). C.W.B. is funded by the NIH ( U19A135972 , R01GM134366 , U01DA051972 , and U01AI150748 ). S.P. is supported by the Wu Tsai Human Performance Alliance and the Joe and Clara Tsai Foundation and an unrestricted gift from Barbara Friedman. E.A.H. received funding from EDUC2-08388 Cal Poly San Luis Obispo . N.G.C. is funded by the Doris Duke Foundation (2020081) and by NIH K08 NS109200 . Selected figures were generated using BioRender . This study was approved by the UC San Diego Institutional Review Board (IRB-190699). Funding Information: A.M. is funded by the NIH. He reports income from Livanova, Equillium, and Corvus related to medical education. ResMed provided a philanthropic donation to UC San Diego. S.C. has consulted for Avalia, Roche, and GlaxoSmithKline. Funding Information: We are grateful to patients and their families for participation. We also thank the nurses in the UC San Diego-affiliated Medical Center ICU and the step-down unit for assistance. We thank Dr. Christopher K. Glass and Dr. Sven Heinz for advice. This work was supported by the NGS Core Facility of the Salk Institute with funding from NIH-NCI CCSG: P30 014195, the Chapman Foundation, and the Helmsley Charitable Trust. M.T.Y.L. is supported by the Academic Sleep Pulmonary Integrated Research/Clinical Fellowship through the American Thoracic Society, NIH (5T32HL134632-04), and Veterans Affair (1IK2BX005908). M.F.O. is supported by the NIH/National Institute of General Medical Science (T32GM121318). R.K.A. is funded by NIH K99/R00 AI145762. S.C. is funded by NIH/Cooperative Centers on Human Immunology (U19AI142742). S.H.D. is supported by NIH (R00 GM135515). C.W.B. is funded by the NIH (U19A135972, R01GM134366, U01DA051972, and U01AI150748). S.P. is supported by the Wu Tsai Human Performance Alliance and the Joe and Clara Tsai Foundation and an unrestricted gift from Barbara Friedman. E.A.H. received funding from EDUC2-08388 Cal Poly San Luis Obispo. N.G.C. is funded by the Doris Duke Foundation (2020081) and by NIH K08 NS109200. Selected figures were generated using BioRender. This study was approved by the UC San Diego Institutional Review Board (IRB-190699). C.W.B. M.T.Y.L. and N.G.C. conceived the study. J.F. and N.G.C. oversaw the trial's logistics. M.F.O. M.T.Y.L. and N.G.C. identified, enrolled, and obtained consent from patients. M.F.O. M.T.Y.L. M.R. M.H. M.A. and K.P. collected patient samples. E.A.H. C.T.N. S.T. R.K. M.T.Y.L. S.D. and N.G.C. processed samples. M.F.O. M.T.Y.L. A.P. L.E.C.A. K.P. and N.G.C. gathered and interpreted the clinical data. S.H.D. generated csRNA-seq libraries. H.D.L. generated total RNA-seq libraries. M.W.C. processed the sequencing data. C.W.B. M.W.C. M.T.Y.L. and S.H.D. analyzed and interpreted the csRNA-seq and total RNA-seq dataset. S.I.R. J.M.D. R.K.A. and S.C. performed the cytokine analysis. A.S.W. and N.G.C. performed the CMap analysis. A.M. and S.P. provided critical feedback on the study design and the manuscript. N.G.C. M.T.Y.L. and C.W.B. interpreted data and wrote the manuscript with input from all authors. A.M. is funded by the NIH. He reports income from Livanova, Equillium, and Corvus related to medical education. ResMed provided a philanthropic donation to UC San Diego. S.C. has consulted for Avalia, Roche, and GlaxoSmithKline. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023",
year = "2023",
month = feb,
day = "21",
doi = "10.1016/j.xcrm.2023.100935",
language = "English (US)",
volume = "4",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "2",
}