title: Integrative model of genomic factors for determining binding site selection by estrogen receptor-α.
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.
authors.affiliation: Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
authors.forename: Roy
authors.initials: R
authors.lastname: Joseph
authors.forename: Yuriy L
authors.initials: YL
authors.lastname: Orlov
authors.forename: Mikael
authors.initials: M
authors.lastname: Huss
authors.forename: Wenjie
authors.initials: W
authors.lastname: Sun
authors.forename: Say Li
authors.initials: SL
authors.lastname: Kong
authors.forename: Leena
authors.initials: L
authors.lastname: Ukil
authors.forename: You Fu
authors.initials: YF
authors.lastname: Pan
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Lim
authors.forename: Jane S
authors.initials: JS
authors.lastname: Thomsen
authors.forename: Yijun
authors.initials: Y
authors.lastname: Ruan
authors.forename: Neil D
authors.initials: ND
authors.lastname: Clarke
authors.forename: Shyam
authors.initials: S
authors.lastname: Prabhakar
authors.forename: Edwin
authors.initials: E
authors.lastname: Cheung
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051541:Hepatocyte Nuclear Factor 3-alpha; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D011485:Protein Binding; D012319:RNA Polymerase II / Q000378:metabolism; D020218:Response Elements; D014157:Transcription Factors / Q000378:metabolism*; D024363:Transcription Initiation Site
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D051541:Hepatocyte Nuclear Factor 3-alpha; D008024:Ligands; D014157:Transcription Factors; D012319:RNA Polymerase II