Integrative model of genomic factors for determining binding site selection by estrogen receptor-α

Mol Syst Biol. 2010 Dec 21;6:456. doi: 10.1038/msb.2010.109.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites
  • Cell Line
  • Cell Line, Tumor
  • Chromatin / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Estrogen Receptor alpha / chemistry
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Hepatocyte Nuclear Factor 3-alpha
  • Humans
  • Ligands
  • Models, Biological
  • Protein Binding
  • RNA Polymerase II / metabolism
  • Response Elements
  • Transcription Factors / metabolism*
  • Transcription Initiation Site

Substances

  • Chromatin
  • DNA-Binding Proteins
  • Estrogen Receptor alpha
  • Hepatocyte Nuclear Factor 3-alpha
  • Ligands
  • Transcription Factors
  • RNA Polymerase II