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| Status |
Public on Mar 26, 2024 |
| Title |
Redirecting the pioneering function of FOXA1 with covalent small molecules [ChIP-seq] |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
ChIP-seq experiments for profiling the impact of stereoprobes treatments on FOXA1 localization in parental 22Rv1 cells or engineered 22Rv1 cells stably expressing Y36C-PHF5A with dox-inducible WT-FOXA1 or C258A-FOXA1 expression.
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| Contributor(s) |
Erb MA, Zhang Y, Cravatt BF, Won S |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Mar 18, 2024 |
| Last update date |
Mar 26, 2024 |
| Contact name |
Yuxiang Zhang |
| E-mail(s) |
zyx2719@gmail.com
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| Organization name |
The Scripps Research Institute
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| Department |
Chemistry
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| Lab |
Erb Lab
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| Street address |
10550 N. Torrey Pines Rd.
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| City |
La Jolla |
| State/province |
CA |
| ZIP/Postal code |
92037 |
| Country |
USA |
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| Platforms (1) |
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| Samples (15)
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| GSM8152264 |
22Rv1-parental, WX-02-23, FOXA1 |
| GSM8152265 |
22Rv1-parental, WX-02-43, FOXA1 |
| GSM8152266 |
22Rv1-parental, siFOXA1, FOXA1 |
| GSM8152267 |
22Rv1-parental, si-control, FOXA1 |
| GSM8152268 |
22Rv1-FOXA1-WT, Input |
| GSM8152269 |
22Rv1-FOXA1-WT, noDox, FOXA1 |
| GSM8152270 |
22Rv1-FOXA1-WT, DMSO, FOXA1 |
| GSM8152271 |
22Rv1-FOXA1-WT, WX-02-23, FOXA1 |
| GSM8152272 |
22Rv1-FOXA1-C258A, Input |
| GSM8152273 |
22Rv1-FOXA1-C258A, noDox, FOXA1 |
| GSM8152274 |
22Rv1-FOXA1-C258A, DMSO, FOXA1 |
| GSM8152275 |
22Rv1-FOXA1-C258A, WX-02-23, FOXA1 |
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| Relations |
| BioProject |
PRJNA1089117 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE261803_RAW.tar |
791.2 Mb |
(http)(custom) |
TAR (of BED, WIG) |
SRA Run Selector |
| Raw data are available in SRA |
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