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Association with YY1 and the PRC2 complex mediates the transcriptional repressive functions of YAP/TEAD

ABSTRACT: Inhibition of cell proliferation through cell-cell contact (contact-inhibition or CI) is a major mechanism regulating development and homeostasis in multicellular organisms. However, the molecular mechanisms mediating CI remain largely unknown. The Hippo pathway has emerged as a central regulator of organ size and tissue homeostasis, by controlling the localization and activity of the transcriptional regulator YAP. As previous studies indicated YAP is regulated by cell-cell contact, we assessed the function of YAP in this context. Here we show that in addition to its function as a transcriptional activator, YAP functions as a repressor of a significant number of genes including the cyclin-dependent kinase (Cdk) inhibitor p27. We find that inhibition of p27 depends on the Ying-Yang 1 (YY1) transcription factor and recruitment of the Polycomb repressive complex (PRC2). Moreover, YAP marks co-localizes with YY1 and EZH2 marks on the genome to transcriptionally repress a network of genes mediating a host of cellular functions, including key regulators of the cell cycle. This work highlights a broad and underappreciated aspect of YAP function as a transcriptional repressor and details a mechanism through which these functions are mediated.

ORGANISM(S): Homo sapiens

PROVIDER: GSE112932 | GEO | 2021/04/06

REPOSITORIES: GEO

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Project description:Regulation of organ size is important for development and tissue homeostasis. In Drosophila, Hippo signaling controls organ size by regulating the activity of a TEAD transcription factor, Scalloped, through modulation of its coactivator protein Yki. The role of mammalian Tead proteins in growth regulation, however, remains unknown. Here we examined the role of mouse Tead proteins in growth regulation. In NIH3T3 cells, cell density and Hippo signaling regulated the activity of Tead proteins by modulating nuclear localization of a Yki homologue, Yap, and the resulting change in Tead activity altered cell proliferation. Tead2-VP16 mimicked Yap overexpression, including increased cell proliferation, reduced cell death, promotion of EMT, lack of cell contact inhibition, and promotion of tumor formation. Growth promoting activities of various Yap mutants correlated with their Tead-coactivator activities. Tead2-VP16 and Yap regulated largely overlapping sets of genes. However, only a few of the Tead/Yapregulated genes in NIH3T3 cells were affected in Tead1-/-;Tead2-/- or Yap-/- embryos. Most of the previously identified Yap-regulated genes were not affected in NIH3T3 cells or mutant mice. In embryos, levels of nuclear Yap and Tead1 varied depending on cell types. Strong nuclear accumulation of Yap and Tead1 were seen in myocardium, correlating with requirements of Tead1 for proliferation. However, their distribution did not always correlate with proliferation. Taken together, mammalian Tead proteins regulate cell proliferation and contact inhibition as a transcriptional mediator of Hippo signaling, but the mechanisms by which Tead/Yap regulate cell proliferation differ depending on cell types, and Tead, Yap and Hippo signaling may play multiple roles in mouse embryos. We used microarrays to know the gene expression profiles regurated by Tead2-VP16, Tead2-EnR, Yap, and cell density in NIH3T3 cells. Keywords: Cell density, genetic modification Tead2-VP16-, Tead2-EnR-, Yap- and control vector-expressing cells were cultured at low or high density for RNA extraction and hybridization on Affymetrix microarrays.

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Association with YY1 and the PRC2 complex mediates the transcriptional repressive functions of YAP/TEAD

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