Chem-map profiles drug binding to chromatin in cells

  • Nat Biotechnol. 2023 Jan 23. doi: 10.1038/s41587-022-01636-0.
Zutao Yu  #  1 ,  Jochen Spiegel  #  1 ,  Larry Melidis  2 ,  Winnie W I Hui  2 ,  Xiaoyun Zhang  1 ,  Antanas Radzevičius  1 ,  Shankar Balasubramanian  3  4  5
Affiliations
  • 1. Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
  • 2. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • 3. Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK. [email protected].
  • 4. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. [email protected].
  • 5. School of Clinical Medicine, University of Cambridge, Cambridge, UK. [email protected].
  • # Contributed equally.
PMID: 36690761 DOI: 10.1038/s41587-022-01636-0
Abstract

Characterizing drug-target engagement is essential to understand how small molecules influence cellular functions. Here we present Chem-map for in situ mapping of small molecules that interact with DNA or chromatin-associated proteins, utilizing small-molecule-directed transposase Tn5 tagmentation. We demonstrate Chem-map for three distinct drug-binding modalities as follows: molecules that target a chromatin protein, a DNA secondary structure or that intercalate in DNA. We map the BET bromodomain protein-binding inhibitor JQ1 and provide interaction maps for DNA G-quadruplex structure-binding molecules PDS and PhenDC3. Moreover, we determine the binding sites of the widely used Anticancer drug doxorubicin in human leukemia cells; using the Chem-map of doxorubicin in cells exposed to the histone deacetylase inhibitor tucidinostat reveals the potential clinical advantages of this combination therapy. In situ mapping with Chem-map of small-molecule interactions with DNA and chromatin proteins provides insights that will enhance understanding of genome and chromatin function and therapeutic interventions.

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