Global reference mapping of human transcription factor footprints

Area of Science:

• Genomics
• Molecular Biology
• Epigenetics

Background:

• Transcription factor binding to DNA regulates gene expression.
• Genetic variations in regulatory DNA are linked to diseases and traits.
• Identifying functional regulatory variants is challenging.

Purpose of the Study:

• To comprehensively map transcription factor footprints across the human genome.
• To understand the role of DNA accessibility and transcription factor occupancy in gene regulation.
• To investigate the impact of genetic variation on regulatory elements.

Main Methods:

• Generated high-density DNase I cleavage maps from 243 human cell/tissue types.
• Integrated data to delineate millions of transcription factor occupancy sites at nucleotide resolution.
• Analyzed the relationship between genetic variants, footprints, and regulatory element accessibility.

Main Results:

• Delineated ~4.5 million transcription factor occupancy sites genome-wide.
• Found that cis-regulation is mainly modulated by DNA accessibility, not differential TF occupancy.
• Showed that disease-associated variants are enriched within footprints, with near-equal loss/gain-of-function alleles.
• Discovered increased genetic variation density within footprints, suggesting a role in cis-regulatory evolution.

Conclusions:

• Provides a high-resolution map of transcription factor binding sites.
• Offers a framework for analyzing gene regulatory mechanisms and functional genetic variation.
• Highlights the importance of regulatory footprints in understanding human disease and evolution.