Integrative model of genomic factors for determining binding site selection by estrogen receptor-α.
Mol Syst Biol, 2010/12/21;6:456.
Joseph R[1], Orlov YL, Huss M, Sun W, Kong SL, Ukil L, Pan YF, Li G, Lim M, Thomsen JS, Ruan Y, Clarke ND, Prabhakar S, Cheung E, Liu ET
Affiliations
PMID: 21179027DOI: 10.1038/msb.2010.109
Impact factor: 13.068
Abstract
A major question in transcription factor (TF) biology is why a TF binds to only a small fraction of motif eligible binding sites in the genome. Using the estrogen receptor-α as a model system, we sought to explicitly define parameters that determine TF-binding site selection. By examining 12 genetic and epigenetic parameters, we find that an energetically favorable estrogen response element (ERE) motif sequence, co-occupancy by the TF FOXA1, the presence of the H3K4me1 mark and an open chromatin configuration in the pre-ligand state provide specificity for ER binding. These factors can model estrogen-induced ER binding with high accuracy (ROC-AUC=0.95 and 0.88 using different genomic backgrounds). Moreover, when assessed in another estrogen-responsive cell line, this model was highly predictive for ERα binding (ROC-AUC=0.86). Variance in binding site selection between MCF-7 and T47D resides in sites with suboptimal ERE motifs, but modulated by the chromatin configuration. These results suggest a definable interplay between sequence motifs and local chromatin in selecting TF binding.
MeSH terms
Base Sequence; Binding Sites; Cell Line; Cell Line, Tumor; Chromatin; DNA-Binding Proteins; Estrogen Receptor alpha; Hepatocyte Nuclear Factor 3-alpha; Humans; Ligands; Models, Biological; Protein Binding; RNA Polymerase II; Response Elements; Transcription Factors; Transcription Initiation Site
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