Dissecting FOXA1 pioneering function by acute pharmacological degradation

Area of Science:

• Molecular Biology
• Cancer Biology
• Epigenetics

Background:

• Pioneer factors, such as FOXA1, are crucial for controlling gene transcription by modifying chromatin accessibility.
• Studying pioneer factor activity with kinetic precision has been limited by a lack of suitable chemical tools.
• FOXA1 is a key factor in the progression of breast and prostate cancers.

Purpose of the Study:

• To develop novel chemical tools for precise kinetic studies of FOXA1 activity.
• To investigate the precise role of FOXA1 in chromatin remodeling and gene transcription.
• To understand how FOXA1's pioneering activity influences cancer-relevant transcriptional programs.

Main Methods:

• Development of a dTAG-based system for small molecule-induced degradation of FOXA1.
• Coupling pharmacological perturbations with rapid measurements of chromatin structure and function.
• Analysis of genomic localization, chromatin accessibility, and gene expression changes following FOXA1 modulation.

Main Results:

• FOXA1 exclusively initiates chromatin opening at its specific genomic binding sites.
• This chromatin opening by FOXA1 can lead to both gene activation and repression, depending on the surrounding chromatin environment.
• These regulatory effects were observed for androgen receptor (AR) target genes and other cancer-associated genes.

Conclusions:

• The developed dTAG system provides a powerful chemical tool for dissecting FOXA1's function with kinetic precision.
• FOXA1's pioneering activity has a context-dependent effect on gene transcription, leading to both activation and repression.
• Understanding these regulatory mechanisms is critical for developing targeted therapies for FOXA1-driven cancers.