Genome-Wide Characterization of TAZ Binding Sites in Mammary Epithelial Cells

Simple Summary: The protein TAZ plays an important role in the Hippo signaling pathway that regulates important biological processes such as cell proliferation, controlled cell death, cancer stem cell traits, tumorigenesis, and resistance to therapies. Specifically, TAZ functions as a transcription coactivator that influences the transcription of various genes. Despite the importance of TAZ, genome-wide occupancy sites for TAZ remain poorly defined. Here, a tetracycline (tet)-inducible gene expression system was used to turn on TAZ activation in mammary epithelial cells, and we characterized genome-wide binding sites at different TAZ activation time points. We found that most TAZ binds to distant enhancer and non-coding regions of genes at earlier TAZ activation time points and binding shifts to nearby promoter regions of genes at later TAZ activation time points. We also found that TAZ activation results in chromatin architecture alterations. These results could lead to the identification of new therapeutic targets for breast cancer. The transcriptional co-activator with PDZ binding motif (TAZ) is a key effector of the Hippo signaling pathway. We and others previously reported that high expression levels of TAZ are positively associated with decreased survival rates and shorter times to relapse in basal-like breast cancer (BLBC) patients. The oncogenic activity of TAZ involves the regulation of diverse signal transduction pathways that direct processes such as cell proliferation, migration, and resistance to apoptosis, albeit through poorly characterized gene expression programs. Here, using a tet-inducible system in mammary epithelial MCF10A cells, we have characterized the TAZ-regulated transcription program using RNA sequencing in a temporal and spatial manner. We further identified global TAZ binding sites at different TAZ activation time points by chromatin immunoprecipitation (ChIP) sequencing analysis. We found that the vast majority of TAZ was rapidly localized in enhancer regions at the early TAZ activation time point and then gradually spread to promoter regions. TAZ bound to enhancer regions following a switch in potential TEAD and FOSL2 transcription factor motifs. Furthermore, the ATAC sequencing analysis indicated that TAZ activation led to chromatin structural alterations. Together, our results have revealed the landscape of genome-wide TAZ binding sites and may lead to improvements in the current understanding of how TAZ regulates the gene expression program that contributes to the development of breast cancer.

Automated summary

The protein TAZ plays a crucial role in the Hippo signaling pathway and its activation leads to binding to enhancer and non-coding regions, as well as chromatin structural alterations. This study provides important insights into the mechanism by which TAZ regulates gene expression and its potential role in breast cancer therapy.