Chem-map profiles drug binding to chromatin in cells.
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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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Acknowledgements: We thank D. Tannahill from Cambridge University, UK and S. Aparicio from British Columbia Cancer Research Centre, Canada for their helpful discussion and comments on the manuscript. We thank the staff at the Genomic Core Facility at the Cancer Research UK Cambridge Institute for assistance with sequencing experiments. We thank P. Gierth (NMR Facility) for assistance in the NMR analysis. This work was financially supported by program grant funding from Cancer Research UK (C9681/A29214), core funding from Cancer Research UK (C9545/A19836) and Herchel Smith funds. S.B. is a Wellcome Trust Senior Investigator (209441/Z/17/Z).
Funder: Core funding from Cancer Research UK (C9545/A19836) and Herchel Smith funds. S.B. is a Wellcome Trust Senior Investigator (209441/Z/17/Z)
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1546-1696
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Cancer Research UK (C9681/A29214)
Wellcome Trust (209441/Z/17/Z)
Cancer Research UK (19836)