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PRBB-CRG Sessions Arnold Berk

PRBB-CRG Sessions Arnold Berk

25/03/2019
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PRBB-CRG Sessions Arnold Berk

MARIE CURIE

25/03/201912:00MARIE CURIEPRBB-CRG SessionsArnold BerkUniversity of California, Los Angeles | UCLA · Molecular Biology Institute (MBI), USA"The YAP & TAZ of the Hippo pathway, a viral oncogene and cellular differentiation”Host: Miguel Beato (CRG)Abstract:Adenovirus-transformed cells have a de-differentiated phenotype. Eliminating E1A in Ad5-transformed human embryonic kidney cells (mostly mesenchymal stem cells, MSC), de-repressed ~2600 genes, generating a gene expression profile closely resembling MSC. This was associated with a dramatic change in cell morphology from one with scant cytoplasm and a globular nucleus to one with increased cytoplasm, extensive actin stress fibers and actomyosin-dependent flattening against the substratum. E1A-induced histone hypoacetylation by p300/CBP at H3K27/18 was reversed. Remarkably, most of the increase in H3K27/18ac was near TEAD transcription factors associated with their co-activators YAP and TAZ regulated by the Hippo pathway. E1A causes YAP/TAZ cytoplasmic sequestration. After eliminating E1A, YAP/TAZ were transported into nuclei where they associated with poised enhancers with DNA-bound TEAD4 and H3K4me1. This activation of YAP/TAZ required Rho-family GTPase signaling and caused p300/CBP histone acetylation, chromatin remodeling, and cohesin loading to establish MSC-associated enhancers and then super-enhancers. Consistent results were also observed in rat embryo cells, and human fibroblasts and respiratory tract epithelial cells. These results together with earlier studies suggest how YAP and TAZ function in a developmental check-point controlled by signaling from the actin cytoskeleton preventing terminal differentiation until a cell is in the correct cellular and tissue environment.