A biochemical screening platform to target chromatin states using condensates as a tool

Area of Science:

• Epigenetics and molecular biology
• Drug discovery and development
• Biophysics and biochemistry

Background:

• Dysfunctional chromatin states drive disease, but targeting individual proteins leads to toxicity.
• Current drug discovery lacks methods to target complex, multivalent protein interactions within chromatin states.
• Chromatin forms functional condensates via specific, weak multivalent interactions.

Purpose of the Study:

• To develop a new screening method for identifying modulators of dysfunctional chromatin states.
• To address the technology gap in targeting context-dependent protein-protein interactions (PPIs) within chromatin.
• To enable specific targeting of disease-driving chromatin assemblies for improved therapeutic outcomes.

Main Methods:

• Recreating distinct chromatin contexts as phase-separated condensates with unique biochemical and biophysical properties.
• Developing a scalable screening platform based on these chromatin condensates.
• Identifying small molecules that modulate chromatin states based on their specific context.

Main Results:

• Successfully recreated diverse chromatin contexts in phase-separated condensates.
• Established a functional screening platform for identifying chromatin modulators.
• Identified small molecules exhibiting context-specific modulation of chromatin states.

Conclusions:

• The developed screening method allows for specific targeting of disease-driving chromatin assemblies.
• This approach promises to reduce off-target effects and improve clinical translation.
• Opens new therapeutic avenues for targeting complex, multivalent interactions in disease.