Dynamic Activity in cis-Regulatory Elements of Leukocytes Identifies Transcription Factor Activation and Stratifies COVID-19 Severity in ICU Patients [RNA-seq]

The transcription factors programs mediating the immune response to COVID-19 and disease outcomes are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped-small (cs)RNA-seq, in contrast to capturing the steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factors activity and regulatory pathways. Here, we profile the acute changes in transcription initiation in peripheral leukocytes from critically ill COVID-19 patients, thereby identifying transcription factor (TF) motifs that track the severity of COVID19-associated lung injury, disease resolution, and outcome. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the regulation of specific pathways, cell types, and the combinatorial activity of transcription factors. We find evidence of critical roles for regulatory networks driven by signal-dependent and lineage determining transcription factors, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes and associated with single nucleotide genetic variants implicated in COVID-19 susceptibility. 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. Overall design: Comparison of transcriptional activity over time among COVID-19 patients with varying disease severity. Total RNA was obtained from whole blood samples.