CCCTC-binding factor acts upstream of FOXA1 and demarcates the genomic response to estrogen.

Transcription activation by estrogen receptor (ER) is rapid and dynamic. How the prompt and precise ER response is established and maintained is still not fully understood. Here, we report that two boundary elements surrounding the well defined ERalpha target TFF1 locus are occupied by the CCCTC-binding factor (CTCF). These elements are separated by 40 kb but cluster in the nuclear space depending on CTCF but independent of estrogen and transcription. In contrast, in estrogen non-responsive breast cancer cells, the spatial proximity of these two elements is lost and the entire locus instead displays a polycomb repressive complex 2-controlled heterochromatin characteristic. We showed that CTCF acts upstream of the "pioneer" factor FOXA1 in determining the genomic response to estrogen. We propose that the CTCF-bound boundary elements demarcate active versus inactive regions, building a framework of adjacent chromosome territory that predisposes ERalpha-regulated transcription.