PXD050685-1

PXD050685 is an original dataset announced via ProteomeXchange.

Title	Redirecting the pioneering function of FOXA1 with covalent small molecules
Description	Pioneer transcription factors (TFs) exhibit a special ability to 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 electrophilic small molecules that stereoselectively and site-specifically bind the pioneer TF, 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 covalent ligands relax the canonical DNA binding preference of FOXA1 by strengthening interactions with suboptimal ancillary 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.
HostingRepository	PRIDE
AnnounceDate	2024-09-05
AnnouncementXML	Submission_2024-09-05_15:56:12.530.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sang Joon Won
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-16 15:50:47	ID requested
⏵ 1	2024-09-05 15:56:12	announced

Dataset with its publication pending

submitter keyword: FOXA1, ABPP, cysteine, proteomics, chemical probe

Benjamin F. Cravatt
contact affiliation	Department of Chemistry, The Scripps Research Institute, USA
contact email	cravatt@scripps.edu
lab head
Sang Joon Won
contact affiliation	The Scripps Research Institute
contact email	swon@scripps.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/09/PXD050685

PRIDE project URI

• PRIDE
  1. PXD050685
     1. Label: PRIDE project
     2. Name: Redirecting the pioneering function of FOXA1 with covalent small molecules