Journal
MOLECULAR SYSTEMS BIOLOGY
Volume 6, Issue -, Pages -Publisher
WILEY
DOI: 10.1038/msb.2010.109
Keywords
chromatin; DNA binding; modeling; recognition motifs; transcription factor
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Funding
- A*STAR of Singapore
- European Community [FP6-018652]
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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-alpha 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 ER alpha 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. Molecular Systems Biology 6: 456; published online 21 December 2010; doi:10.1038/msb.2010.109
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