Redirecting the pioneering function of FOXA1 with covalent small molecules.

Autor:	Won SJ; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA., Zhang Y; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA., Reinhardt CJ; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA., Hargis LM; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA., MacRae NS; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA., DeMeester KE; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA., Njomen E; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA., Remsberg JR; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA., Melillo B; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA., Cravatt BF; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: cravatt@scripps.edu., Erb MA; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: michaelerb@scripps.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2024 Nov 07; Vol. 84 (21), pp. 4125-4141.e10. Date of Electronic Publication: 2024 Oct 15.
DOI:	10.1016/j.molcel.2024.09.024
Abstrakt:	Pioneer transcription factors (TFs) bind to and open closed chromatin, facilitating engagement by other regulatory factors involved in gene activation or repression. Chemical probes are lacking for pioneer TFs, which has hindered their mechanistic investigation in cells. Here, we report the chemical proteomic discovery of electrophilic compounds that stereoselectively and site-specifically bind the pioneer TF forkhead box protein A1 (FOXA1) at a cysteine (C258) within the forkhead DNA-binding domain. We show that these covalent ligands react with FOXA1 in a DNA-dependent manner and rapidly remodel its pioneer activity in prostate cancer cells reflected in redistribution of FOXA1 binding across the genome and directionally correlated changes in chromatin accessibility. Motif analysis supports a mechanism where the ligands relax the canonical DNA-binding preference of FOXA1 by strengthening interactions with suboptimal sequences in predicted proximity to C258. Our findings reveal a striking plasticity underpinning the pioneering function of FOXA1 that can be controlled by small molecules. Competing Interests: Declaration of interests B.F.C. is a scientific advisor to Vividion Therapeutics. M.A.E. holds equity in Nexo Therapeutics and serves on their scientific advisory board. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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