title: AP-2γ regulates oestrogen receptor-mediated long-range chromatin interaction and gene transcription.
abstract: Oestrogen receptor α (ERα) is key player in the progression of breast cancer. Recently, the cistrome and interactome of ERα were mapped in breast cancer cells, revealing the importance of spatial organization in oestrogen-mediated transcription. However, the underlying mechanism of this process is unclear. Here, we show that ERα binding sites (ERBS) identified from the Chromatin Interaction Analysis-Paired End DiTag of ERα are enriched for AP-2 motifs. We demonstrate the transcription factor, AP-2γ, which has been implicated in breast cancer oncogenesis, binds to ERBS in a ligand-independent manner. Furthermore, perturbation of AP-2γ expression impaired ERα DNA binding, long-range chromatin interactions, and gene transcription. In genome-wide analyses, we show that a large number of AP-2γ and ERα binding events converge together across the genome. The majority of these shared regions are also occupied by the pioneer factor, FoxA1. Molecular studies indicate there is functional interplay between AP-2γ and FoxA1. Finally, we show that most ERBS associated with long-range chromatin interactions are colocalized with AP-2γ and FoxA1. Together, our results suggest AP-2γ is a novel collaborative factor in ERα-mediated transcription.
authors.affiliation: Cancer Biology and Pharmacology, Genome Institute of Singapore, A STAR (Agency for Science, Technology and Research), Singapore.
authors.forename: Si Kee
authors.initials: SK
authors.lastname: Tan
authors.forename: Zhen Hua
authors.initials: ZH
authors.lastname: Lin
authors.forename: Cheng Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: Vipin
authors.initials: V
authors.lastname: Varang
authors.forename: Kern Rei
authors.initials: KR
authors.lastname: Chng
authors.forename: You Fu
authors.initials: YF
authors.lastname: Pan
authors.forename: Eu Leong
authors.initials: EL
authors.lastname: Yong
authors.forename: Wing Kin
authors.initials: WK
authors.lastname: Sung
authors.forename: Win King
authors.initials: WK
authors.lastname: Sung
authors.forename: Edwin
authors.initials: E
authors.lastname: Cheung
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D046228:Microarray Analysis; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D020218:Response Elements / Q000235:genetics; D050656:Transcription Factor AP-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D002843:Chromatin; D047628:Estrogen Receptor alpha; D034741:RNA, Small Interfering; D050656:Transcription Factor AP-2