Decoding mutational hotspots in human disease through the gene modules governing thymic regulatory T cells

Area of Science:

• Immunology
• Genomics
• Computational Biology

Background:

• Regulatory T cells (Tregs) are crucial for immune homeostasis and preventing autoimmune diseases.
• Complex immune-mediated disorders often have a multigenic basis, requiring advanced analytical tools.
• Computational strategies for multi-omics data are needed for clinical applications in immunology.

Purpose of the Study:

• To quantify the differential Transcription Factor (TF) occupancy landscape in human thymic Tregs.
• To uncover Gene Regulatory Modules (GRMs) governing lineage-committed Tregs.
• To assess the utility of GRMs for prioritizing genetic variants in complex diseases.

Main Methods:

• Combined RNA-sequencing (RNA-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq).
• Generated a matrix of differential TF binding to differentially expressed genes in Tregs versus conventional CD4 thymocytes.
• Analyzed enrichment of rare variants in gene loci identified by GRMs in patients with common variable immunodeficiency.

Main Results:

• Identified GRMs governing lineage-committed Tregs in the human thymus.
• Gene loci within GRMs were significantly enriched for rare variants in common variable immunodeficiency patients.
• Demonstrated the potential of GRMs to link genetic variations to disease phenotypes.

Conclusions:

• The developed GRMs are a valuable resource for variant classification in polygenic diseases.
• GRMs can aid in identifying novel therapeutic targets for immune-mediated disorders.
• The computational strategy is broadly applicable to other biological processes for deciphering mutational hotspots.