YAP/TAZ transcriptional program in breast cancer cells

Once YAP/TAZ have been activated by any upstream input, they shuttle into the nucleus and pair with DNA-binding proteins to interact with DNA and activate the transcription of their target genes. Recently, we have been exploring the global transcriptional program of YAP/TAZ in breast cancer cells (MDA-MB-231), by combining gene expression profiling and ChIP-seq (Chromatin immunoprecipitation coupled with deep sequencing). We have identified a few general rules that govern YAP/TAZ recruitment on chromatin; these same “guidelines” for YAP/TAZ nuclear activity have emerged from independent studies by Galli et al, 2015, and Stein et al., 2015. The first rule is that YAP/TAZ are recruited to TEAD binding sites, as predicted by the model of CTGF promoter. The second rule is that YAP/TAZ are to a great extent recruited to enhancers that are located far away from target promoters; this is a feature of YAP/TAZ transcriptional activity that couldn’t be appreciated without a genome-wide approach. YAP/TAZ-occupied enhancers bear the marks of active chromatin (H3K27 acetylation, nucleosome depletion). We walked back on chromatin loops to match target genes with YAP/TAZ-occupied enhancers. It turned out that YAP/TAZ drive the expression of a complex transcriptional program, one third of which is dedicated to the regulation of cell growth, in line with YAP/TAZ biological role in cancer cells. The third rule is that YAP/TAZ/TEAD are often part of a larger complex of transcription factors, and sit on enhancers next to AP-1 (Activator Protein 1) dimers. YAP/TAZ/TEAD and AP-1 jointly regulate the expression of a set of common target genes, so that AP-1 factors potentiate the activation of YAP/TAZ oncogenic growth program in mammary epithelial cells.

Click here for anti-YAP/TAZ ChIP-Seq (credit: Zanconato et al, 2015).

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