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Fat cadherin cleavage releases a transcriptionally active nuclear fragment to regulate target gene expression [ChIP-Seq]

ABSTRACT: The atypical cadherin fat (ft) controls growth, planar cell polarity (PCP) tissue organization, and mitochondrial function, in organisms ranging from fruit flies to mammals. Working at the apical-junctional plasma membrane, the intracellular domain of the Ft protein, FtICD, binds to and regulates components of the Hippo and PCP pathways. Unexpectedly, we find that a fragment of the FtICD is present in the nucleus in cultured cells as well as in embryonic and larval tissues, and we identify nuclear localization and nuclear export signals in FtICD required for this localization. We show that membrane-bound FtICD is cleaved and enters nuclei in vivo. Using endogenously tagged Ft as well as overexpressed FtICD, we conducted ChIP-seq experiments and identified putative Ft targets, including genes involved in signaling pathways, chromatin organization, pattern formation, and neural development. RNAseq demonstrates that some of these genes are dysregulated in ft mutants. We observe strong co-localization of Ft binding regions with peaks for other factors such as DREF and BEAF-32, as well as the Hippo pathway components Yorkie (Yki) and Scalloped (Sd), suggesting that Ft may act in conjunction with these factors to regulate gene expression. Supporting this hypothesis, we found that Ft physiclly interacts with both Yki and Sd in co-immunoprecipitation experients in S2 cells. We propose that the modulation of Hippo pathway activity constitutes one of the nuclear functions of Ft, complementing its estalished function as an upstream regulator of Hippo signaling.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE308417 | GEO | 2025/09/25

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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Fat cadherin cleavage releases a transcriptionally active nuclear fragment to regulate target gene expression [ChIP-Seq]

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