학술논문
Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients
Document Type
article
Author
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
Source
Cell Reports Medicine. 4(2)
Subject
Language
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.