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Dishevelled-1 regulates global transcriptomic changes in MDA-MB-231 triple negative breast cancer cells (RNA-Seq).

ABSTRACT: Dishevelled (DVL) is a crucial component of the Wnt-signaling pathway and is vital for multiple physiological processes. Previously thought to have a primarily cytoplasmic role, the discovery of DVL translocation to the nucleus reframed how DVL is viewed functionally. Despite our advances in elucidating DVL nuclear function, further investigation is needed to determine its transcriptomic and epigenetic regulatory abilities. We show here that modification of DVL1 expression globally affects the transcriptomic landscape. Additionally, analysis of DVL1 ChIP-seq allowed us to map global binding sites and reveal the extensive reach of DVL1 binding sites. Integration of RNA-Sequencing and ChIP-Sequencing further revealed DVL1 transcription factor binding partners to regulate gene expression. These findings provide insight to nuclear DVL1 regulation of gene transcription.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249322 | GEO | 2024/08/30

REPOSITORIES: GEO

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Dishevelled-1 regulates global transcriptomic changes in MDA-MB-231 triple negative breast cancer cells (ChIP-Seq).

Project description:Dishevelled (DVL) is a crucial component of the Wnt-signaling pathway and is vital for multiple physiological processes. Previously thought to have a primarily cytoplasmic role, the discovery of DVL translocation to the nucleus reframed how DVL is viewed functionally. Despite our advances in elucidating DVL nuclear function, further investigation is needed to determine its transcriptomic and epigenetic regulatory abilities. We show here that modification of DVL1 expression globally affects the transcriptomic landscape. Additionally, analysis of DVL1 ChIP-seq allowed us to map global binding sites and reveal the extensive reach of DVL1 binding sites. Integration of RNA-Sequencing and ChIP-Sequencing further revealed DVL1 transcription factor binding partners to regulate gene expression. These findings provide insight to nuclear DVL1 regulation of gene transcription.

2024-08-30 | GSE249320 | GEO

RNAseq experiment to identify differentially expressed genes in dvl/rtfl mutants and DVL overexpresion lines in inflorescence apices of Arabidopsis thaliana

Project description:The lack of visible phenotypes of multiple dvl/rtfl mutants prompted us to compare the transcriptomic signatures of inflorescence apices of wildtype and mutant combinations (specifically dvl1 dvl8 dvl11 rtfl11 dvl19 and dvl8 dvl11 rtfl9 rtfl11 dvl19), as well as dvl1-D mutant, where DVL1 is overexpressed, and 35Spro:DVL8 line. Significant changes in gene expression were caused by the mutation of DVL genes in both quintuple mutant and overexpression backgrounds.

2023-09-19 | GSE243205 | GEO

Dishevelled-3 protein conformation dynamics analyzed by FRET-based biosensors reveals a key role of casein kinase 1

Project description:Dishevelled (DVL) is the key component of the Wnt signaling pathway. Currently, DVL conformational dynamics under native conditions is unknown. To overcome this limitation, we developed the Fluorescein Arsenical Hairpin Binder- (FlAsH-) based FRET in vivo approach to study DVL conformation in living cells. Using this single-cell FRET approach, we demonstrate that (i) Wnt ligands induce open DVL conformation, (ii) DVL variants that are predominantly open, show more even subcellular localization and more efficient membrane recruitment by Frizzled (FZD) and (iii) Casein Kinase 1 ɛ (CK1ɛ) has a key regulatory function in DVL conformational dynamics. In silico modeling and in vitro biophysical methods explain how CK1ɛ-specific phosphorylation events control DVL conformations via modulation of the PDZ domain and its interaction with DVL C-terminus. In summary, our study describes an experimental tool for DVL conformational sampling in living cells and elucidates the essential regulatory role of CK1ɛ in DVL conformational dynamics.

2019-04-02 | PXD013085 | Pride

Huwe1-mediated ubiquitylation of Dvl defines a novel negative feedback loop in the Wnt signaling pathway

Project description:Wnt signaling plays a central role in development, adult tissue homeostasis and cancer. Several steps in the canonical Wnt/b-catenin signaling cascade are regulated by ubiquitylation, a protein modification that influences the stability, subcellular localization or protein-protein interactions of target proteins. To identify novel regulators of the Wnt/b-catenin pathway, we performed RNAi screens in C. elegans and human tissue culture cells and identified the HECT domain containing ubiquitin ligase eel-1/Huwe1 as a negative regulator of Wnt signaling. Huwe1 functions cell autonomously in signal-receiving cells and genetically acts upstream of b-catenin. Mechanistically, Huwe1 binds to and ubiquitylates the cytoplasmic Wnt pathway component Dishevelled (Dvl) in a Wnt3a and CK1e dependent manner. Huwe1 mediated ubiquitylation does not target Dvl for degradation. Instead, we found that Huwe1 decreases Dvl signaling by inhibiting Dvl multimerization. We conclude that Huwe1 is part of an evolutionarily conserved negative feedback loop in the Wnt/b-catenin pathway

2014-05-28 | PXD000781 | Pride

Comparative phosphorylation map of Dishevelled 3 links phospho-signatures to biological outputs.

Project description:Background: Dishevelled (DVL) is an essential component of the Wnt signaling cascades. Function of DVL is controlled by phosphorylation but the molecular details are missing. DVL3 contains 131 serines and threonines whose phosphorylation generates complex barcodes underlying diverse DVL3 functions. In order to dissect the role of DVL phosphorylation we analyzed the phosphorylation of human DVL3 induced by previously reported (CK1ε, NEK2, PLK1, CK2α, RIPK4, PKCδ) and newly identified (TTBK2, Aurora A) DVL kinases. Methods: Shotgun proteomics including TiO2 enrichment of phosphorylated peptides followed by liquid chromatography tandem mass spectrometry on immunoprecipitates from HEK293T cells was used to identify and quantify phosphorylation of DVL3 protein induced by 8 kinases. Functional characterization was performed by in-cell analysis of phospho-mimicking/non phosphorylatable DVL3 mutants and supported by FRET assays and NMR spectroscopy. Results: We used quantitative mass spectrometry and calculated site occupancies and quantified phosphorylation of >80 residues. Functional validation demonstrated the importance of CK1ε-induced phosphorylation of S268 and S311 for Wnt-3a-induced β-catenin activation. S630-643 cluster phosphorylation by CK1, NEK2 or TTBK2 is essential for even subcellular distribution of DVL3 when induced by CK1 and TTBK2 but not by NEK2. Further investigation showed that NEK2 utilizes a different mechanism to promote even localization of DVL3. NEK2 triggered phosphorylation of PDZ domain at S263 and S280 prevents binding of DVL terminus to PDZ and promotes an open conformation of DVL3 that is more prone to even subcellular localization. Conclusions: We identify unique phosphorylation barcodes associated with DVL function. Our data provide an example of functional synergy between phosphorylation in structured domains and unstructured IDRs that together dictate the biological outcome.

2020-01-09 | PXD015963 | Pride

Shade-induced RTFL/DVL peptides negatively regulate the shade response by directly interacting with BSKs in Arabidopsis

Project description:For shade-intolerant species, shade light indicates the close proximity of neighboring plants and triggers the shade avoidance syndrome (SAS), which causes exaggerated growth and reduced crop yield. We report that nonsecreted ROT FOUR LIKE (RTFL)/DEVIL (DVL) peptides negatively regulate the SAS by repressing the activities of BRASSINOSTEROID SIGNALING KINASEs (BSKs) and PHYTOCHROME INTERACTING FACTOR 4 (PIF4) in Arabidopsis. To identify RTFL function during SAS, we performed RNA-seq to search for differentially expressed genes (DEGs) by comparing transcript levels between Col-0 and dvl1-1D, bsk36, or pif47 seedlings during white light and shade conditions.

2023-09-28 | GSE226205 | GEO

The exon junction complex regulates the splicing of cell polarity gene dlg1 to control Wingless signaling in development

Project description:Wingless (Wg)/Wnt signaling is conserved in all metazoan animals and plays critical roles in development. The Wg/Wnt morphogen reception is essential for signal activation, whose activity is mediated through the receptor complex and a scaffold protein Dishevelled (Dsh). We report here that the exon junction complex (EJC) activity is indispensable for Wg signaling by maintaining an appropriate level of Dsh protein for Wg ligand reception in Drosophila. Transcriptome analyses in Drosophila wing imaginal discs indicate that the EJC controls the splicing of the cell polarity gene disc large 1 (dlg1), whose coding protein directly interacts with Dsh. Genetic and biochemical experiments demonstrate that Dlg1 protein acts independently from its role in cell polarity to protect Dsh protein from lysosomal degradation. More importantly, human orthologous Dlg protein is sufficient to promote Dvl protein stabilization and Wnt signaling activity, thus revealing a conserved regulatory mechanism of Wg/Wnt signaling by Dlg and EJC. whole transcriptome RNA-seq to examine mRNAs extracted from wildtype (i.e. overexpressing lacZ) and pre-EJC-defective (i.e. overexpressing tsu RNAi) wing discs, respectively.

2016-08-19 | E-GEOD-81220 | biostudies-arrayexpress

Gene expression in colon cancer cell lines

Project description:Genetic and epigenetic defects in Wnt/ß-catenin signaling play important roles in colorectal cancer progression. Here we identify DACT3, a member of the DACT (Dpr/Frodo) gene family, as a negative regulator of Wnt/ß-catenin signaling that is transcriptionally repressed in colorectal cancer. Unlike other Wnt signaling inhibitors that are silenced by DNA methylation, DACT3 repression is associated with bivalent histone modifications. Remarkably, DACT3 expression can be robustly de-repressed by a pharmacological combination that simultaneously targets both histone methylation and deacetylation, leading to strong inhibition of Dishevelled (Dvl)-mediated Wnt/ß-catenin signaling and massive apoptosis of colorectal cancer cells. Our study identifies DACT3 as an important regulator of Wnt/ß-catenin signaling in colorectal cancer and suggests a potential strategy for therapeutic control of Wnt/ß-catenin signaling in colorectal cancer. Keywords: Colon cancer cell line

2008-03-29 | GSE10952 | GEO

Colon cancer

Project description:Genetic and epigenetic defects in Wnt/?-catenin signaling play important roles in colorectal cancer progression. Here we identify DACT3, a member of the DACT (Dpr/Frodo) gene family, as a negative regulator of Wnt/ß-catenin signaling that is transcriptionally repressed in colorectal cancer. Unlike other Wnt signaling inhibitors that are silenced by DNA methylation, DACT3 repression is associated with bivalent histone modifications. Remarkably, DACT3 expression can be robustly de-repressed by a pharmacological combination that simultaneously targets both histone methylation and deacetylation, leading to strong inhibition of Dishevelled (Dvl)-mediated Wnt/?-catenin signaling and massive apoptosis of colorectal cancer cells. Our study identifies DACT3 as an important regulator of Wnt/ß-catenin signaling in colorectal cancer and suggests a potential strategy for therapeutic control of Wnt/ß-catenin signaling in colorectal cancer. This SuperSeries is composed of the SubSeries listed below.

2008-03-29 | GSE10972 | GEO

Global expression profiling of Arabidopsis plants overexpressing a member of the DEVIL gene family.

Project description:The DEVIL (DVL) family is a plant-specific family of genes that encode predicted small polypeptides (Wen, et al., 2004; Narita, et al., 2004). Overexpression of DVL family members in Arabidopsis results in pleiotropic developmental phenotypes including shortened stature, rounded rosette leaves, clustered inflorescences, shortened pedicles and horn-like protrusions at the distal end of siliques. Point mutations reveled that a conserved C-terminal domain is required for DVL overexpression phenotypes and is conserved in all family members. Based on the overexpression experiments, DVL family members are suggested to play important roles in plant development. In an attempt to uncover genes whose transcription was changed in response to DVL overexpression, we designed a microarray-based global profiling experiment. A transgenic Arabidopsis line that carried a GVG construct (glucocorticoid inducible) (Aoyama and Chua, 1997) driving the expression of DVL4 was generated and used in this experiment. This allowed for better identification of primary transcriptional responses to DVL overexpression. Experiments with transgenic lines in which DVL overexpression is driven by a constitutive promoter would add the complexity of secondary transcriptional responses as well. Computational analysis of the datasets generated in this experiment lead to the identification of genes that may be involved in responding to DVL overexpression. Experimentation is currently ongoing to investigate the role these genes play in plant development and the DVL overexpression phenotypes.

2009-08-01 | GSE8975 | GEO

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