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Redirecting the pioneering function of FOXA1 with covalent small molecules

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Prostate Adenocarcinoma,Lymphoma

SUBMITTER: Sang Joon Won

LAB HEAD: Benjamin F. Cravatt

PROVIDER: PXD050685 | Pride | 2024-09-05

REPOSITORIES: Pride

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			Action	DRS
	20200827_22RV1_20uMWX2_V1to10_01.raw	Raw
	20200827_22RV1_20uMWX2_V1to10_02.raw	Raw
	20200827_22RV1_20uMWX2_V1to10_03.raw	Raw
	20200827_22RV1_20uMWX2_V1to10_04.raw	Raw
	20200827_22RV1_20uMWX2_V1to10_05.raw	Raw

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