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Profiling chromatin accessibility responses in human neutrophils with sensitive pathogen detection
Nikhil Ram-Mohan1, Simone A Thair1, Ulrike M Litzenburger2
1Department of Emergency Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Life Science Alliance
|June 19, 2021
Summary
Profiling neutrophil epigenetic responses to pathogens can aid sepsis recognition. Early epigenetic changes in neutrophils reveal timely and challenge-specific transcriptional regulation mechanisms.
Area of Science:
- Immunology
- Genomics
- Molecular Biology
Background:
- Sepsis is a global health threat, often stemming from bloodstream infections and characterized by dysregulated host immune responses.
- Neutrophils play a critical role in host defense against pathogens and preventing organ damage during infection.
- Understanding early host responses at the epigenetic level could improve sepsis diagnosis and management.
Purpose of the Study:
- To investigate early host epigenetic responses in human neutrophils upon challenge with various pathogens and ligands.
- To characterize the dynamics of chromatin accessibility and gene expression changes in neutrophils during infection.
- To identify distinct mechanisms of transcriptional regulation in neutrophils during innate immune activation.
Main Methods:
- Assay for transposase-accessible chromatin sequencing (ATAC-seq) was performed on human neutrophils stimulated with toll-like receptor ligands and microbial organisms.
- RNA sequencing (RNA-seq) was conducted on neutrophils exposed to Escherichia coli at 1 and 4 hours post-exposure.
- Integration of ATAC-seq and RNA-seq data to map epigenetic changes to gene expression.
Main Results:
- ATAC-seq successfully detected pathogen DNA within neutrophils.
- While differential chromatin changes showed similar genomic distributions, overlaps between different challenges were minimal, indicating unique responses.
- Epigenomic changes were dynamic, with only a small subset of changes shared across Escherichia coli challenges over time, leading to varied gene expression patterns.
- Three distinct classes of gene regulation were identified based on chromatin accessibility changes in promoters and distal enhancers.
- Transcription factor footprinting revealed specific temporal and challenge-dependent regulatory mechanisms.
Conclusions:
- Early neutrophil epigenetic profiling provides insights into host responses to pathogens.
- Neutrophil responses to different immune stimuli are largely unique, highlighting the complexity of innate immunity.
- The study elucidates distinct mechanisms of neutrophil transcriptional regulation, offering potential targets for sepsis intervention.
