RNAseq analysis of osteosarcoma cell line with overexpression of YAP-S94A and YAP-S127A
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE184003 | GEO | 2021/09/16
REPOSITORIES: GEO
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Project description:Throughout Metazoa, developmental processes are controlled by a surprisingly limited number of conserved signaling pathways. Precisely how these signaling cassettes were assembled in early animal evolution remains poorly understood, as do the molecular transitions that potentiated the acquisition of their myriad developmental functions. Here we analyze the molecular evolution of the proto-oncogene YAP/Yorkie, a key effector of the Hippo signaling pathway that controls organ size in both Drosophila and mammals. Based on heterologous functional analysis of evolutionarily distant Yap/Yorkie orthologs, we demonstrate that a structurally distinct interaction interface between Yap/Yorkie and its partner TEAD/Scalloped became fixed in the eumetazoan common ancestor. We then combine transcriptional profiling of tissues expressing phylogenetically diverse forms of Yap/Yorkie with ChIP-seq validation in order to identify a common downstream gene expression program underlying the control of tissue growth in Drosophila. Intriguingly, a subset of the newly-identified Yorkie target genes are also induced by Yap in mammalian tissues, thus revealing a conserved Yap-dependent gene expression signature likely to mediate organ size control throughout bilaterian animals. Combined, these experiments provide new mechanistic insights while revealing the ancient evolutionary history of Hippo signaling. We sought to define the downstream target genes of selected Yap variants by performing RNA sequencing analysis (RNA-seq) on total RNA isolated from GMR-Gal4>Yap eye discs. Transcriptional profiles were generated in triplicate from eye imaginal disks with either endogenous Yki, or GMR-Gal4 over-expressed Yki, Trichoplax Yap, Monosiga Yap, or Monisiga Yap+TEAD domain, using deep sequencing via Illumina Hi Seq.
2014-03-01 | E-GEOD-54600 | biostudies-arrayexpress
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.
2008-11-20 | E-GEOD-12498 | biostudies-arrayexpress
Project description:YAP1 (Yes-associated protein 1) is transcriptional co-activator that partners with the TEAD family of transcription factors to regulate gene expression. Increased YAP-TEAD activity is strongly implicated in the development, progression, and metastasis of several cancer types including melanoma, but the YAP-TEAD target genes that are responsible for YAP-TEAD-dependent melanoma progression and metastasis are largely unknown. To identify YAP-TEAD regulated genes in metastatic melanoma cells we used RNA-sequencing to compare gene expression in control A375 human melanoma cells to A375 cells expressing mutant forms of YAP with increased transcriptional activity due to the mutation of LATS inhibitory phosphorylation sites (YAPS127A or YAPS127A,S381A). To determine which YAP-dependent gene expression changes are mediated by TEADs we also included a mutant form of YAP that is unable to bind TEADS (YAPS94A,S127A).
2024-03-29 | GSE234083 | GEO
Project description:This study compares gene expression change upon expression of Yes-associated protein (YAP) wild-type or mutants in order to establish the importance of TEAD binding and WW domains in the gene-induction function of YAP. The results indicate that gene-induction is seriously comprised in YAP-S94A (TEAD binding domain mutant) expressing cells. And mutantion of WW domains (YAP-W1W2) also affect a fraction of YAP induced genes. Therefore both TEAD binding domain and WW domains are required for the full function of YAP in gene-induction. Experiment Overall Design: Four samples are included: 1. pQCXIH vector control; 2 YAP-WT expression; 3. YAP-S94A expression; 4. YAP-W1W2 expression. Gene expression profiles of YAP wild-type or mutants expressing cells were compared to that of vector control. Experiments were done in MCF10A mammary epithelial cells.
2010-01-19 | E-GEOD-13218 | biostudies-arrayexpress
Project description:Angiogenesis, the process by which endothelial cells (ECs) form new blood vessels from existing ones, is intimately linked to the tissue's metabolic milieu and often occurs at nutrient-deficient sites. However, ECs rely on sufficient metabolic resources to support growth and proliferation. How endothelial nutrient acquisition and usage are regulated is unknown. Here we show that these processes are dictated by YAP/TAZ-TEAD – a transcriptional module whose function is highly responsive to changes in the tissue environment. ECs lacking YAP/TAZ or their transcriptional partners, TEAD1, 2, and 4 fail to divide, resulting in stunted vascular growth in mice. Conversely, activation of TAZ, the more abundant paralogue in ECs, boosts proliferation, leading to vascular hyperplasia. We find that YAP/TAZ promote angiogenesis by fueling nutrient mTORC1 signaling. By orchestrating the transcription of a repertoire of cell-surface transporters, YAP/TAZ-TEAD stimulate the import of amino acids and other essential nutrients, thereby enabling mTORC1 pathway activation. Dissociating mTORC1 from these nutrient inputs – elicited by the loss of Rag GTPases – inhibits mTORC1 activity and prevents YAP/TAZ-dependent vascular growth. These findings define a pivotal role for YAP/TAZ-TEAD in steering endothelial mTORC1 and illustrate the essentiality of coordinated nutrient fluxes in the vasculature.
2022-05-08 | PXD026872 | Pride
Project description:The transcriptional coactivators YAP/TAZ are the critical downstream regulators of the Hippo pathway that regulate gene expression in response to changes in pathway activity, mainly by binding to TEAD transcription factors. Uncontrolled transcriptional output of YAP/TAZ can lead to rapid induction of aggressive tumor growth. AP-1 is a dimeric basic leucine zipper (bZIP) transcription factor complex with JUN and FOS proteins being the most abundant members of this family. Unlike FOS, JUN can also form homodimers, but in the cell, JUN presumably preferentially forms heterodimers with members of the FOS family, which act as potent transcriptional activators. Previous studies identified substantial co-occupancy of YAP/TAZ and AP-1 at genomic sites, and they demonstrated that JUN/FOS heterodimers cooperate with the YAP/TAZ and TEAD transcription factors to drive YAP/TAZ target gene expression. Here, we now elucidate a negative feedback mechanism in which high YAP activity is restrained by the recruitment of homodimeric JUN::JUN/NCOR1 repressor complexes and show that this noncanonical JUN function is part of a tumor suppressor mechanism in the liver.
2024-06-30 | GSE235963 | GEO
Project description:The transcriptional coactivators YAP/TAZ are the critical downstream regulators of the Hippo pathway that regulate gene expression in response to changes in pathway activity, mainly by binding to TEAD transcription factors. Uncontrolled transcriptional output of YAP/TAZ can lead to rapid induction of aggressive tumor growth. AP-1 is a dimeric basic leucine zipper (bZIP) transcription factor complex with JUN and FOS proteins being the most abundant members of this family. Unlike FOS, JUN can also form homodimers, but in the cell, JUN presumably preferentially forms heterodimers with members of the FOS family, which act as potent transcriptional activators. Previous studies identified substantial co-occupancy of YAP/TAZ and AP-1 at genomic sites, and they demonstrated that JUN/FOS heterodimers cooperate with the YAP/TAZ and TEAD transcription factors to drive YAP/TAZ target gene expression. Here, we now elucidate a negative feedback mechanism in which high YAP activity is restrained by the recruitment of homodimeric JUN::JUN/NCOR1 repressor complexes and show that this noncanonical JUN function is part of a tumor suppressor mechanism in the liver.
2024-06-30 | GSE235616 | GEO
Project description:The transcriptional coactivators YAP/TAZ are the critical downstream regulators of the Hippo pathway that regulate gene expression in response to changes in pathway activity, mainly by binding to TEAD transcription factors. Uncontrolled transcriptional output of YAP/TAZ can lead to rapid induction of aggressive tumor growth. AP-1 is a dimeric basic leucine zipper (bZIP) transcription factor complex with JUN and FOS proteins being the most abundant members of this family. Unlike FOS, JUN can also form homodimers, but in the cell, JUN presumably preferentially forms heterodimers with members of the FOS family, which act as potent transcriptional activators. Previous studies identified substantial co-occupancy of YAP/TAZ and AP-1 at genomic sites, and they demonstrated that JUN/FOS heterodimers cooperate with the YAP/TAZ and TEAD transcription factors to drive YAP/TAZ target gene expression. Here, we now elucidate a negative feedback mechanism in which high YAP activity is restrained by the recruitment of homodimeric JUN::JUN/NCOR1 repressor complexes and show that this noncanonical JUN function is part of a tumor suppressor mechanism in the liver.
2024-06-30 | GSE235615 | GEO
Project description:The transcriptional coactivators YAP/TAZ are the critical downstream regulators of the Hippo pathway that regulate gene expression in response to changes in pathway activity, mainly by binding to TEAD transcription factors. Uncontrolled transcriptional output of YAP/TAZ can lead to rapid induction of aggressive tumor growth. AP-1 is a dimeric basic leucine zipper (bZIP) transcription factor complex with JUN and FOS proteins being the most abundant members of this family. Unlike FOS, JUN can also form homodimers, but in the cell, JUN presumably preferentially forms heterodimers with members of the FOS family, which act as potent transcriptional activators. Previous studies identified substantial co-occupancy of YAP/TAZ and AP-1 at genomic sites, and they demonstrated that JUN/FOS heterodimers cooperate with the YAP/TAZ and TEAD transcription factors to drive YAP/TAZ target gene expression. Here, we now elucidate a negative feedback mechanism in which high YAP activity is restrained by the recruitment of homodimeric JUN::JUN/NCOR1 repressor complexes and show that this noncanonical JUN function is part of a tumor suppressor mechanism in the liver.
2024-06-30 | GSE235614 | GEO
Project description:The transcriptional coactivators YAP/TAZ are the critical downstream regulators of the Hippo pathway that regulate gene expression in response to changes in pathway activity, mainly by binding to TEAD transcription factors. Uncontrolled transcriptional output of YAP/TAZ can lead to rapid induction of aggressive tumor growth. AP-1 is a dimeric basic leucine zipper (bZIP) transcription factor complex with JUN and FOS proteins being the most abundant members of this family. Unlike FOS, JUN can also form homodimers, but in the cell, JUN presumably preferentially forms heterodimers with members of the FOS family, which act as potent transcriptional activators. Previous studies identified substantial co-occupancy of YAP/TAZ and AP-1 at genomic sites, and they demonstrated that JUN/FOS heterodimers cooperate with the YAP/TAZ and TEAD transcription factors to drive YAP/TAZ target gene expression. Here, we now elucidate a negative feedback mechanism in which high YAP activity is restrained by the recruitment of homodimeric JUN::JUN/NCOR1 repressor complexes and show that this noncanonical JUN function is part of a tumor suppressor mechanism in the liver.
2024-06-30 | GSE235613 | GEO