Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients
Michael T. Lam, Sascha H. Duttke, Mazen Odish, Hiep D. Le, Emily A. Hansen, Celina T. Nguyen, Samantha Trescott, Roy Kim, Shaunak Deota, Max W. Chang, Arjun Patel, Mark Hepokoski, Mona Alotaibi, Mark Rolfsen, Katherine Perofsky, Anna S. Warden, Jennifer Foley, Sydney I. Ramirez, Jennifer M. Dan, Robert Abbott, Shane Crotty, Laura E. Crotty Alexander, Anil K. Malhotra, Satchidananda Panda, Christopher Benner, Nicole G. Coufal
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.