Effect of ZBTB18 on gene expression and chromatin organization [ATAC-seq]

This study set out to delineate gene expression programs that are differentially modulated in metastatic breast cancer cells with high versus low ability to further metastasize. To this end, the gene expression profiles of E0771GFP cells, M11GFP and M12GFP cells were determined. Analysis of these data sets identified ZBTB18 as a transcriptional repressor with lower activity in tumor cells that retain a high metastatic potential. To determine how ZBTB18 affects gene expression and chromatin organization, ZBTB18 was overexpressed in E0771GFP breast cancer cells. Gene expression profiles and differentially accessible DNA regions analyses were performed and identified Tgfbr2 as one of the genes most significantly repressed by ZBTB18. To determine the contribution of the TGFb1 -TGFBR2 signaling axis towards ZBTB18-mediated effects, E0771GFP cells overexpressing ZBTB18 were transduced with a doxycycline-inducible Tgfbr2 construct. These cells were then treated with doxycycline and recombinant TGFb1 or vehicle control and gene expression profiles were determined. These studies revealed that inhibition of ZBTB18 activity in tumor cells promotes metastasis by increasing chromatin accessibility and by enabling pro-metastatic TGFb1-TGFBR2-driven changes. Overall design: This project aims at identifying the global changes in gene expression and open chromatin regions between ZBTB18-overexpressing and control mouse cancer cell lines.