tetano
Editor, Senior Moderator
Cell Rep Med
. 2023 Jan 25;100935.
doi: 10.1016/j.xcrm.2023.100935. Online ahead of print.
Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients
Michael Tun Yin Lam[SUP] 1 [/SUP], Sascha H Duttke[SUP] 2 [/SUP], Mazen F Odish[SUP] 3 [/SUP], Hiep D Le[SUP] 4 [/SUP], Emily A Hansen[SUP] 5 [/SUP], Celina T Nguyen[SUP] 6 [/SUP], Samantha Trescott[SUP] 5 [/SUP], Roy Kim[SUP] 5 [/SUP], Shaunak Deota[SUP] 4 [/SUP], Max W Chang[SUP] 7 [/SUP], Arjun Patel[SUP] 3 [/SUP], Mark Hepokoski[SUP] 3 [/SUP], Mona Alotaibi[SUP] 3 [/SUP], Mark Rolfsen[SUP] 8 [/SUP], Katherine Perofsky[SUP] 9 [/SUP], Anna S Warden[SUP] 6 [/SUP], Jennifer Foley[SUP] 10 [/SUP], Sydney I Ramirez[SUP] 11 [/SUP], Jennifer M Dan[SUP] 11 [/SUP], Robert K Abbott[SUP] 12 [/SUP], Shane Crotty[SUP] 11 [/SUP], Laura E Crotty Alexander[SUP] 13 [/SUP], Atul Malhotra[SUP] 3 [/SUP], Satchidananda Panda[SUP] 4 [/SUP], Christopher W Benner[SUP] 7 [/SUP], Nicole G Coufal[SUP] 14 [/SUP]
Affiliations
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.
Keywords: COVID-19; active cistrome; acute respiratory distress syndrome; biomarkers; critical care; disease stratification; endotyping; enhancer RNA; transcription factor activity; transcriptional regulation.
. 2023 Jan 25;100935.
doi: 10.1016/j.xcrm.2023.100935. Online ahead of print.
Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients
Michael Tun Yin Lam[SUP] 1 [/SUP], Sascha H Duttke[SUP] 2 [/SUP], Mazen F Odish[SUP] 3 [/SUP], Hiep D Le[SUP] 4 [/SUP], Emily A Hansen[SUP] 5 [/SUP], Celina T Nguyen[SUP] 6 [/SUP], Samantha Trescott[SUP] 5 [/SUP], Roy Kim[SUP] 5 [/SUP], Shaunak Deota[SUP] 4 [/SUP], Max W Chang[SUP] 7 [/SUP], Arjun Patel[SUP] 3 [/SUP], Mark Hepokoski[SUP] 3 [/SUP], Mona Alotaibi[SUP] 3 [/SUP], Mark Rolfsen[SUP] 8 [/SUP], Katherine Perofsky[SUP] 9 [/SUP], Anna S Warden[SUP] 6 [/SUP], Jennifer Foley[SUP] 10 [/SUP], Sydney I Ramirez[SUP] 11 [/SUP], Jennifer M Dan[SUP] 11 [/SUP], Robert K Abbott[SUP] 12 [/SUP], Shane Crotty[SUP] 11 [/SUP], Laura E Crotty Alexander[SUP] 13 [/SUP], Atul Malhotra[SUP] 3 [/SUP], Satchidananda Panda[SUP] 4 [/SUP], Christopher W Benner[SUP] 7 [/SUP], Nicole G Coufal[SUP] 14 [/SUP]
Affiliations
- PMID: 36758547
- DOI: 10.1016/j.xcrm.2023.100935
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.
Keywords: COVID-19; active cistrome; acute respiratory distress syndrome; biomarkers; critical care; disease stratification; endotyping; enhancer RNA; transcription factor activity; transcriptional regulation.