Genetic integration with cell-specific nucleosome positioning resolves causal relationships underlying chromatin...

Area of Science:

• Genomics
• Epigenetics
• Human Genetics

Background:

• Cell type-specific chromatin accessibility QTL (caQTL) mapping is crucial for understanding genetic regulation of chromatin and GWAS associations.
• Existing caQTL studies lack resolution, failing to differentiate nucleosome-free regions (NFRs) from positioned nucleosomes.

Purpose of the Study:

• To develop and apply a statistical model to decompose ATAC-seq profiles into NFRs and phased nucleosomes.
• To map cell type-specific genetic effects on NFRs (nfrQTLs) and nucleosome occupancy (nucQTLs) in human skeletal muscle.
• To investigate the causal relationship between nfrQTLs and nucQTLs in shaping chromatin profiles.

Main Methods:

• Utilized statistical modeling of ATAC-seq fragment position and length to distinguish NFRs and nucleosomes.
• Applied single nucleus (sn)ATAC-seq on 281 human muscle biopsies.
• Performed colocalization and causal inference analyses between nfrQTLs and nucQTLs.

Main Results:

• Identified 76,027 nfrQTLs and 24,623 nucQTLs across skeletal muscle cell types.
• Demonstrated that nfrQTLs are significantly more likely to causally influence nucQTLs and adjacent nucleosome phasing.
• Hundreds of nfrQTLs colocalized with GWAS signals for muscle-related traits, with many mapping to nfrPeaks.

Conclusions:

• The developed method enhances resolution in caQTL mapping by distinguishing NFRs and nucleosome occupancy.
• nfrQTLs play a primary role in initiating regulatory effects by altering NFR accessibility, subsequently influencing broader chromatin landscapes.
• This approach provides mechanistic insights into how genetic variants impact gene expression and complex traits through chromatin modifications.