Activator protein-2 is a critical determinant of estrogen receptor interactome formation and gene transcription in breast cancer [expression]

Estrogen receptor (ER) is key player in the progression of breast cancer. ER binds to DNA and mediates long-range chromatin interactions throughout the genome, but the underlying mechanism in this process is unclear. Here, we show that AP-2 motifs are highly enriched in the ER binding sites (ERBS) identified from the recent ChIA-PET of ER. More importantly, we demonstrate that AP-2 (also known as TFAP2C), a member of the AP-2 family which has been implicated in breast cancer oncogenesis, is recruited to chromatin in a ligand-independent manner and co-localized with ER binding events. Furthermore, pertubation of AP-2 expression disrupts ER DNA binding, long-range chromatin interactions, and gene transcription. Using ChIP-seq, we show that AP-2 and ER binding occurs in close proximity on a genome-wide scale. The majority of these shared genomic regions are also occupied by the pioneer factor, FoxA1. AP-2 is required for efficient FoxA1 binding and vice versa. Finally, we show that most ERBS associated with long-range chromatin interactions are co-localized with both AP-2 and FoxA1. Together, our results suggest AP-2 is an essential factor in ER-mediated transcription, primarily working together with FoxA1 to facilitate ER binding and long-range chromatin interactions.

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Tan SK, Lin ZH, Chang CW, Varang V, Chng KR, Pan YF, Yong EL, Sung WK, Cheung E