Dynamic regulatory elements in single-cell multimodal data implicate key immune cell states enriched for autoimmune...

Area of Science:

• Immunology
• Genetics
• Computational Biology

Background:

• Autoimmune diseases involve immune system attacks on host tissues.
• Understanding genetic risk variants in specific cell states is crucial for developing targeted therapies.

Purpose of the Study:

• To identify noncoding genomic regions with accessible chromatin linked to cell-state-specific gene expression.
• To determine if cell-state-dependent chromatin accessibility is enriched for autoimmune disease heritability.

Main Methods:

• Multimodal single-nucleus RNA sequencing and ATAC sequencing were performed on 28,674 cells from inflamed synovial tissue.
• A multivariate Poisson model predicted chromatin accessibility peaks from gene expression data.
• Heritability enrichment analysis was conducted for cell-state-dependent versus cell-state-invariant accessibility peaks.

Main Results:

• Cell-state-dependent chromatin accessibility peaks were significantly enriched for heritability across 14 autoimmune diseases compared to cell-state-invariant peaks.
• These dynamic peaks were associated with specific immune cell states, including T peripheral helper, regulatory T, dendritic, and STAT1+CXCL10+ myeloid cells.
• The findings highlight the importance of dynamic regulatory elements in pinpointing disease-critical genetic variations.

Conclusions:

• Dynamic regulatory elements, identified through cell-state-dependent chromatin accessibility, are key to understanding autoimmune disease genetics.
• This approach can precisely identify immune cell states enriched for genetic risk variants, paving the way for novel therapeutic strategies.