Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients.

Autor:	Lam MTY; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Laboratory of Regulatory Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Pulmonary and Critical Care Section, VA San Diego Healthcare System, La Jolla, CA 92161, USA. Electronic address: mtlam@health.ucsd.edu., Duttke SH; School of Molecular Biosciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99163, USA., Odish MF; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Le HD; Laboratory of Regulatory Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Hansen EA; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA., Nguyen CT; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA., Trescott S; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA., Kim R; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA., Deota S; Laboratory of Regulatory Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Chang MW; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Patel A; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Hepokoski M; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Alotaibi M; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Rolfsen M; Internal Medicine Residency Program, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Perofsky K; Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; Rady Children's Hospital, San Diego, CA 92123, USA., Warden AS; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA., Foley J; Rady Children's Hospital, San Diego, CA 92123, USA., Ramirez SI; Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Center for Infectious Diseases and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA., Dan JM; Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Center for Infectious Diseases and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA., Abbott RK; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA., Crotty S; Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Center for Infectious Diseases and Vaccine Research, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA., Crotty Alexander LE; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Pulmonary and Critical Care Section, VA San Diego Healthcare System, La Jolla, CA 92161, USA., Malhotra A; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Panda S; Laboratory of Regulatory Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA., Benner CW; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA., Coufal NG; Sanford Consortium for Regenerative Medicine, La Jolla, CA 92037, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; Rady Children's Hospital, San Diego, CA 92123, USA.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2023 Feb 21; Vol. 4 (2), pp. 100935. Date of Electronic Publication: 2023 Jan 25.
DOI:	10.1016/j.xcrm.2023.100935
Abstrakt:	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. Competing Interests: Declaration of interests 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. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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