A haplotype-resolved view of human gene regulation

Area of Science:

• Genomics
• Epigenetics
• Molecular Biology

Background:

• Diploid human cells possess two distinct genomes, with regulatory variations influencing development and disease.
• Existing methods for cataloging regulatory elements have known and unknown biases, limiting comprehensive analysis.

Purpose of the Study:

• To introduce Fiber-seq Inferred Regulatory Elements (FIRE) for a more comprehensive and quantitative assessment of the accessible chromatin landscape.
• To overcome biases in existing regulatory element catalogs and provide a high-resolution genome-wide map.

Main Methods:

• Development and application of Fiber-seq Inferred Regulatory Elements (FIRE).
• Genome-wide mapping of haplotype-selective chromatin accessibility (HSCA).

Main Results:

• FIRE provides a comprehensive genome-wide map of HSCA, identifying novel imprinted elements, genetic variants disrupting gene regulation, and gene regulatory modules.
• The human leukocyte antigen (HLA) locus shows the highest HSCA in immune cells, with specific transcription factor (TF) binding events disrupted by disease variants.
• Autosomal somatic epimutations are prevalent and mitotically stable, propagating via clonal expansion to create non-genetically deterministic chromatin alterations.

Conclusions:

• FIRE offers a superior method for mapping chromatin accessibility and uncovering regulatory complexities.
• The study reveals the significant role of HSCA and somatic epimutations in human gene regulation, development, and disease pathogenesis.