Genome-scale mapping of variant, enhancer and gene function in primary human CD4+ T cells

Area of Science:

• Immunology
• Genetics
• Systems Biology

Background:

• CD4+ T cells are central to immune disease biology, enriched with genetic risk loci.
• The specific genes and regulatory programs affected by these variants are largely unknown.

Purpose of the Study:

• To identify genes and regulatory programs influenced by immune disease risk variants in CD4+ T cells.
• To establish a framework for tracing the functional impact of noncoding variants.

Main Methods:

• Combined targeted and genome-wide Perturb-seq in primary human CD4+ T cells.
• Analyzed 1,032 cis-regulatory elements (CREs) and 4,724 variants across 14 immune diseases.
• Utilized 4.1 million cells for comprehensive gene and CRE perturbation analysis.

Main Results:

• Identified 626 crucial cis-regulatory element-gene pairs.
• Resolved target genes at the TYK2 and DEXI/CLEC16A loci, linking variants to inflammatory and metabolic programs.
• Revealed shared and disease-specific regulatory programs affected by dispersed variants.

Conclusions:

• Provides a comprehensive framework for variant-to-CRE-to-gene-to-network analysis in disease-relevant cells.
• Advances understanding of the functional consequences of noncoding genetic variation in immune diseases.
• Highlights the importance of CD4+ T cells as a cellular context for immune disease genetics.