Chem-map profiles drug binding to chromatin in cells

Area of Science:

• Molecular Biology
• Genomics
• Pharmacology

Background:

• Understanding how small molecules interact with cellular components like DNA and chromatin proteins is crucial for drug development.
• Current methods for mapping drug-target engagement in situ are limited.

Purpose of the Study:

• To introduce Chem-map, a novel technique for in situ mapping of small molecule interactions with DNA and chromatin-associated proteins.
• To demonstrate the utility of Chem-map across diverse drug-binding modalities.

Main Methods:

• Chem-map utilizes small-molecule-directed transposase Tn5 tagmentation for in situ mapping.
• The method was applied to map inhibitors of chromatin proteins (JQ1), DNA secondary structures (PDS, PhenDC3), and DNA intercalators (doxorubicin).

Main Results:

• Chem-map successfully mapped the interaction sites of JQ1 with BET bromodomain proteins.
• Interaction maps were generated for DNA G-quadruplex binders PDS and PhenDC3.
• Doxorubicin binding sites in human leukemia cells were identified, and combination therapy with tucidinostat showed potential clinical advantages.

Conclusions:

• Chem-map provides high-resolution in situ mapping of small molecule interactions with DNA and chromatin proteins.
• This technique offers valuable insights into genome and chromatin function.
• Chem-map can enhance the understanding and development of therapeutic interventions.