AP-2γ regulates oestrogen receptor-mediated long-range chromatin interaction and gene transcription

Oestrogen receptor a (ER alpha) is key player in the progression of breast cancer. Recently, the cistrome and interactome of ER alpha 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 ER alpha binding sites (ERBS) identified from the Chromatin Interaction Analysis-Paired End DiTag of ER alpha are enriched for AP-2 motifs. We demonstrate the transcription factor, AP-2 gamma, which has been implicated in breast cancer oncogenesis, binds to ERBS in a ligand-independent manner. Furthermore, perturbation of AP-2 gamma expression impaired ER alpha DNA binding, long-range chromatin interactions, and gene transcription. In genome-wide analyses, we show that a large number of AP-2 gamma and ER alpha 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-2 gamma and FoxA1. Finally, we show that most ERBS associated with long-range chromatin interactions are colocalized with AP-2 gamma and FoxA1. Together, our results suggest AP-2 gamma is a novel collaborative factor in ER alpha-mediated transcription. The EMBO Journal (2011) 30, 2569-2581. doi:10.1038/emboj.2011.151; Published online 13 May 2011