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

Michael Tun Yin Lam, Sascha H. Duttke, Mazen F. 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 K. AbbottShane Crotty, Laura E. Crotty Alexander, Atul Malhotra, Satchidananda Panda, Christopher W. Benner, Nicole G. Coufal

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number100935
JournalCell Reports Medicine
Volume4
Issue number2
DOIs
StatePublished - Feb 21 2023

Keywords

  • COVID-19
  • active cistrome
  • acute respiratory distress syndrome
  • biomarkers
  • critical care
  • disease stratification
  • endotyping
  • enhancer RNA
  • transcription factor activity
  • transcriptional regulation

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

Fingerprint

Dive into the research topics of 'Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients'. Together they form a unique fingerprint.

Cite this