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Systematic Dissection of Sequence Features Affecting the Binding Specificity of a Pioneer Factor Reveals Binding Synergy Between FOXA1 and AP-1
- PMID: 37986839
- PMCID: PMC10659273
- DOI: 10.1101/2023.11.08.566246
Systematic Dissection of Sequence Features Affecting the Binding Specificity of a Pioneer Factor Reveals Binding Synergy Between FOXA1 and AP-1
Update in
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Systematic dissection of sequence features affecting binding specificity of a pioneer factor reveals binding synergy between FOXA1 and AP-1.Mol Cell. 2024 Aug 8;84(15):2838-2855.e10. doi: 10.1016/j.molcel.2024.06.022. Epub 2024 Jul 16. Mol Cell. 2024. PMID: 39019045
Abstract
Despite the unique ability of pioneer transcription factors (PFs) to target nucleosomal sites in closed chromatin, they only bind a small fraction of their genomic motifs. The underlying mechanism of this selectivity is not well understood. Here, we design a high-throughput assay called ChIP-ISO to systematically dissect sequence features affecting the binding specificity of a classic PF, FOXA1. Combining ChIP-ISO with in vitro and neural network analyses, we find that 1) FOXA1 binding is strongly affected by co-binding TFs AP-1 and CEBPB, 2) FOXA1 and AP-1 show binding cooperativity in vitro, 3) FOXA1's binding is determined more by local sequences than chromatin context, including eu-/heterochromatin, and 4) AP-1 is partially responsible for differential binding of FOXA1 in different cell types. Our study presents a framework for elucidating genetic rules underlying PF binding specificity and reveals a mechanism for context-specific regulation of its binding.
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