التفاصيل البيبلوغرافية
| العنوان: |
Redirecting the pioneering function of FOXA1 with covalent small molecules. |
| المؤلفون: |
Won SJ, Zhang Y, Reinhardt CJ, MacRae NS, DeMeester KE, Njomen E, Hargis LM, Remsberg JR, Melillo B, Cravatt BF, Erb MA |
| المصدر: |
BioRxiv : the preprint server for biology [bioRxiv] 2024 Mar 21. Date of Electronic Publication: 2024 Mar 21. |
| نوع المنشور: |
Preprint |
| اللغة: |
English |
| بيانات الدورية: |
Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| مستخلص: |
Pioneer transcription factors (TFs) exhibit a specialized 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 the chemical proteomic discovery of 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. |
| معلومات مُعتمدة: |
R35 CA231991 United States CA NCI NIH HHS |
| تواريخ الأحداث: |
Date Created: 20240402 Latest Revision: 20240616 |
| رمز التحديث: |
20240616 |
| مُعرف محوري في PubMed: |
PMC10983899 |
| DOI: |
10.1101/2024.03.21.586158 |
| PMID: |
38562719 |
| قاعدة البيانات: |
MEDLINE |
