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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221067 | GEO | 2023/03/02

REPOSITORIES: GEO

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

Project description: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.

| S-EPMC9874047 | biostudies-literature

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

Project description: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.

2023-03-02 | GSE221066 | GEO

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

2023-03-02 | GSE221065 | GEO

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

Project description:Dynamic Activity in cis-Regulatory Elements of Leukocytes Identifies Transcription Factor Activation and Stratifies COVID-19 Severity in ICU Patients

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

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

| PRJNA912697 | ENA

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

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

| PRJNA912696 | ENA

Profiling Transcription Initiation in Peripheral Leukocytes Reveals Severity-Associated Cis-Regulatory Elements in Critical COVID-19.

Project description:The contribution of transcription factors (TFs) and gene regulatory programs in the immune response to COVID-19 and their relationship to disease outcome is not fully understood. Analysis of genome-wide changes in transcription at both promoter-proximal and distal cis-regulatory DNA elements, collectively termed the 'active cistrome,' offers an unbiased assessment of TF activity identifying key pathways regulated in homeostasis or disease. Here, we profiled the active cistrome from peripheral leukocytes of critically ill COVID-19 patients to identify major regulatory programs and their dynamics during SARS-CoV-2 associated acute respiratory distress syndrome (ARDS). We identified TF motifs that track the severity of COVID- 19 lung injury, disease resolution, and outcome. We used unbiased clustering to reveal distinct cistrome subsets delineating the regulation of pathways, cell types, and the combinatorial activity of TFs. We found critical roles for regulatory networks driven by stimulus and lineage determining TFs, showing that STAT and E2F/MYB regulatory programs targeting myeloid cells are activated in patients with poor disease outcomes and associated with single nucleotide genetic variants implicated in COVID-19 susceptibility. Integration with single-cell RNA-seq found that STAT and E2F/MYB activation converged in specific neutrophils subset found in patients with severe disease. Collectively we demonstrate that cistrome analysis facilitates insight into disease mechanisms and provides an unbiased approach to evaluate global changes in transcription factor activity and stratify patient disease severity.

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SnoRNAs and miRNAs expression profiles underlying COVID-19 disease severity

Project description:The causative organism, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits a wide spectrum of clinical manifestations in disease-ridden patients. Differences in the severity of COVID-19 ranges from asymptomatic infections and mild cases to the severe form, leading to acute respiratory distress syndrome (ARDS) and multiorgan failure with poor survival. MiRNAs can regulate various cellular processes, including proliferation, apoptosis, and differentiation, by binding to the 3′UTR of target mRNAs inducing their degradation, thus serving a fundamental role in post-transcriptional repression. Alterations of miRNA levels in the blood have been described in multiple inflammatory and infectious diseases, including SARS-related coronaviruses. We used microarrays to delineate the miRNAs and snoRNAs signature in the peripheral blood of severe COVID-19 cases (n=9), as compared to mild (n=10) and asymptomatic (n=10) patients, and identified differentially expressed transcripts in severe versus asymptomatic, and others in severe versus mild COVID-19 cases. A cohort of 29 male age-matched patients were selected. All patients were previously diagnosed with COVID-19 using TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific, Waltham, Massachusetts), or Cobas SARS-CoV-2 Test (Roche Diagnostics, Rotkreuz, Switzerland), with a CT value < 30. Additional criterion for selection was age between 35 and 75 years. Participants were grouped into severe, mild and asymptomatic. Classifying severe cases was based on requirement of high-flow oxygen support and ICU admission (n=9). Whereas mild patients were identified based on symptoms and positive radiographic findings with pulmonary involvement (n=10). Patients with no clinical presentation were labelled as asymptomatic cases (n=10).

2022-03-01 | E-MTAB-10970 | biostudies-arrayexpress

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Project description: Not available

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