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Immune disease risk variants regulate gene expression dynamics during CD4+ T cell activation
Blagoje Soskic1,2, Eddie Cano-Gamez1,2, Deborah J Smyth1
1Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK.
This study reveals how genetic variations influence T cell gene expression during activation. Understanding these dynamic gene regulation patterns offers insights into immune-mediated disease susceptibility.
Area of Science:
- Immunology
- Genetics
- Systems Biology
Background:
- T cell activation involves significant gene expression changes crucial for immune responses.
- Genetic variations can influence immune cell function and predispose individuals to immune diseases.
- Understanding gene regulation during T cell activation is key to deciphering disease mechanisms.
Purpose of the Study:
- To map genetic effects on gene expression in CD4+ T cells during activation using single-cell transcriptomics.
- To identify genes dynamically regulated by genetic variation during T cell activation.
- To investigate the link between genetic variants, T cell gene regulation, and immune-mediated diseases.
Main Methods:
- Single-cell RNA sequencing of 655,349 CD4+ T cells from 119 healthy individuals.
- Profiling unstimulated cells and cells at three time points post-activation.
- Expression quantitative trait loci (eQTL) analysis to link genetic variation to gene expression.
Main Results:
- Identified 38 distinct T cell clusters, including transient populations.
- Found 6,407 genes correlated with genetic variation, with 35% showing dynamic regulation during activation.
- Discovered 127 genes regulated by variants linked to immune-mediated diseases, many with dynamic effects.
Conclusions:
- Genetic regulation of T cell gene expression is context-specific and dynamic during activation.
- Dynamic gene regulation by specific variants is enriched for genes associated with immune-mediated diseases.
- This study provides insights into the genetic underpinnings of immune-mediated disease susceptibility.
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