Genome-wide chromatin occupancy of transcription factor TBX2 in luminal breast cancer cells

Here we demonstrate a previously unknown mechanism of TBX2-mediated gene repression in breast tumours, whereby TBX2 physically interacts with CoREST-associated proteins LSD1, HDAC1 and the ZNF217 oncogene. Through Chromatin Immunoprecipitation sequencing (ChIP-seq) we find that while over 80% of TBX2 binding sites are concentrated at promoters, these regions show remarkably no enrichment for the T-box element; rather TBX2-bound regions are biased toward a small number of non-T-box motifs, with the most abundant being Specificity Protein 1 (Sp1), EGR1 and Nuclear Transcription Factor Y (NF-Y). Furthermore, we uncover that Sp1 is crucial for recruitment of TBX2 to the NDRG1 promoter and subsequent repression of this gene. We also observe that ZNF217 cooccupies approximately 30% of TBX2-bound sites, a number of which contain RCOR1 and exhibit upregulation of the associated transcripts following disruption of TBX2/CoREST function. Overall these data highlight a novel potential therapeutic opportunity whereby poor-prognosis, TBX2 overexpressing breast tumours may be pharmacologically exploited by targeting the CoREST-dependent gene repression network, to recover normal growth control. Overall design: Examination of TBX2 genome-wide occupancy in MCF-7 cells by ChIP-seq