The transcription factor Gli3 promotes B cell development in the fetal liver through repression of Shh
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE81467 | GEO | 2017/05/09
SECONDARY ACCESSION(S): PRJNA321725
REPOSITORIES: GEO
Similar Datasets
Project description:Sonic hedgehog (Shh) signals via Gli transcription factors to direct digit number and identity in the vertebrate limb. We have characterized the Gli-dependent cis-regulatory network through a combination of whole genome ChIP-on-chip and transcriptional profiling of the developing mouse limb. In this dataset, we include the expression data obtained from dissected mouse forelimbs using a variety of gain- and loss-of-function hedgehog pathway mutants, as well as limbs dissected into responsive (posterior 2/3ds) and non-responsive (anterior 1/3d) Hh tissues. These data are used to obtain 753 genes that are differentially expressed in response to Shh signaling. Keywords: Comparison of genetic samples 28 Total samples were analyzed. We generated the following pairwise comparisons using PowerExpress: Shh<WT; SmoM2>WT; Gli3<WT; Gli3>WT; Ant<Post; Ant>Post. Genes with an FDRM-bM-^IM-$10% and a fold-change M-bM-^IM-%2 were selected. We did not generate pairwise comparisons for a certain combinations with SmoGli3 and Gli3 mutants because data from these arrays contained significant variability. To identify additional genes that were Shh-responsive, we performed the following multiple sample comparisons using an FDRM-bM-^IM-$10% and a posterior probability cutoff of M-bM-^IM-$25%: 1.) Ant<Post and Shh<WT<SmoM2, 2.) Ant<Post and Shh<WT<SmoM2 and Gli3>SmoGli3, 3.) Ant<Post and Shh<WT<SmoM2 and WT>SmoGli3
2008-09-14 | E-GEOD-11063 | biostudies-arrayexpress
Project description:Purpose: Most Hedgehog responsive gene expression is mediated through GLI de-repression. Additionally GLI -repression is proposed to play roles in limb pre-patterning before HH pathway activation. This study evaluates if GLI repression is established prior to HH pathway activation. Methods: To determine if GLI-repression is established prior to pathway activation, we used genomic approaches to study GLI-mediated repression using the mouse developing limb as a model. We identified pre-HH (E9.25, 21-23S) and post-HH (E10.5, 32-25S) GLI3 binding regions using CUT&RUN for endogenous FLAG-tagged GLI3 proteins. Using a combination of ChIP-seq, CUT&RUN, CUT&Tag, ATAC-seq and RNA-seq, we tested whether loss of Gli3 prior to HH signaling was able to de-repress genes and enhancers, as it does after HH signaling. Results: Prior to HH signaling, GLI3 binds to poised, accessible regions with histone deacetylase (HDAC) proteins, similar to post-HH signaling. Despite GLI3 binding to most regions as it does in the post-HH limb, loss of Gli3 is unable to prematurely active target genes or enhancers. Furthermore, we find that GLI3-dependent chromatin compaction does not occur until roughly 10 hours after HH signaling would have normally been induced. Collectively, these results support that GLI repressor proteins are inert prior to HH pathway activation.
2022-01-21 | GSE178838 | GEO
Project description:Purpose: The response to Hedgehog signaling in the limb is driven by GLI bound enhancers. While most Hh targets in the developing limb bud appear to be regulated by the activity of GLI-repressor, the role of GLI activator in this regulation is unclear. Here we assess the roles of GLI activator and repressor in regulating H3K27ac to activate their enhancers. Methods: ChIP-seq was performed in Embryonic day 10.5 mouse limb buds from WT, Shh-/- and Shh-/-Gli3-/- embryos Results: We found that most GLI binding regions can be activated in the absence of both GLI activator and repressor, while a small subset require GLI activator for activity. These indicate that most GLI enhancers in the limb are regulated by GLI repression.
2020-01-21 | GSE133712 | GEO
Project description:Purpose: The response to Hedgehog signaling in the limb is driven by GLI bound enhancers and the majority of Hh targets in the developing limb bud are regulated solely by the activity of GLI-repressor. Currently we do not have a comprehensive understanding of how GLI bound enhancers respond Hedgehog signaling. The goal of this study is to identify how GLI bound enhancers are regulated by Hedgehog signaling and specifically by GLI-repressor. Methods: ChIP-seq was performed in Embryonic day 10.5 mouse limb buds from mice with endogenously FLAG tagged Gli3. Results: We identified 7282 GLI3 binding regions in the E10.5 limb bud.
2020-01-21 | GSE133710 | GEO
Project description:The Hedgehog signaling pathway is essential for the maintenance and response of several types of stem cells. To study the transcriptional response of stem cells to HH signaling, we searched for proteins binding to GLI proteins, the transcriptional effectors of the HH pathway in mouse embryonic stem (ES) cells. We purified GLI protein complex from an ES cell line that contained a tamoxifen-inducible 3XFLAG-tagged GLI3 repressor allele by anti-FLAG immunoprecipitation and several novel GLI co-factors were identified in the complex by subsequent mass spectrometry analysis.
2016-02-04 | PXD002494 | Pride
Project description:Aberrant activation of Hedgehog (HH) signaling has been identified as a key etiologic factor of many human malignancies. Signal strength, target gene specificity, and oncogenic activity of HH signaling profoundly depend on interactions with other pathways such as epidermal growth factor receptor-mediated signaling which has been shown to cooperate with HH/GLI in basal cell carcinoma and pancreatic cancer. We demonstrate that the human medulloblastoma cell line Daoy possesses a fully inducible endogenous HH pathway. Treatment of Daoy cells with Sonic Hedgehog or Smoothened agonist induced expression of GLI1 protein and prevented processing of GLI3 to its repressor form. To study interactions between HH- and EGF-induced signaling in greater detail, time-resolved measurements were carried out and analyzed on the transcriptomic as well as proteomic level. Daoy cells responded to the co-treatment by downregulating GLI1, PTCH, and HHIP on the transcript level which was also seen when Amphiregulin (AREG) was used instead of EGF. The finding that EGFR signaling silences proteins acting as negative regulators of HH signaling is firstly described here as a novel crosstalk mechanism. Furthermore, combined EGFR/HH signaling maintains high GLI1 protein levels contrasting its downregulation on the transcript level. On the other hand, high level synergism was observed with respect to a strong and significant upregulation of numerous canonical EGF-targets with putative tumor-promoting properties such as MMP7, VEGFA, and IL-8. In conclusion, synergistic effects between EGFR and HH signaling can selectively induce a switch from a canonical HH/GLI profile to a modulated specific target gene profile pointing to more wide-spread, yet context-dependent, interactions between HH/GLI and growth factor receptor signaling in human malignancies. To study interactions between HH- and EGF-induced signaling, time-resolved measurements were carried out over a period of 24 h at 14 different time points after stimulation by EGF with and without additional stimulation by SHH. Furthermore, as a control, cells without any stimulation by EGF and SHH (control) and cells in the presents of SHH were analyzed. Overall, three biological replicates of 60 different treatment/timepoints were analyzed yielding 180 different samples.
2014-07-31 | E-GEOD-46045 | biostudies-arrayexpress
Project description:Hedgehog (Hh) proteins are morphogens which regulate embryonic development and adult tissue homeostasis, with distinct outcomes dependent on the strength and duration of their signals. We show that the Hh signalling pathway modulates the induction and pathology of mouse atopic dermatitis. Sonic hedgehog (Shh) and Hh pathway target genes were upregulated on induction of atopic dermatitis, and the Hh pathway was activated in skin T cells, showing that they respond in vivo to Hh signals secreted from the skin. Shh upregulation reduced skin inflammation in mice, whereas pharmacological Smoothened-inhibition reduced Shh upregulation and exacerbated skin pathology. Hh-signalling to T cells prevented skin inflammation on induction of dermatitis, while inhibition of Hh-mediated transcription in T cells substantially exacerbated the disease. RNA-sequencing analysis of skin CD4+ T cells from mice with chronic atopic dermatitis revealed decreased expression of immune regulatory genes in mice with conditional inhibition of Hh-mediated transcription in T cells, and increased expression of inflammatory and chemokine genes. In contrast, constitutive Hh mediated transcription in T cells led to increased expression of immune regulatory genes in skin CD4+ T cells from mice with chronic atopic dermatitis and protected against inflammation. Hh-mediated transcription in T cells resulted in increased regulatory T (Treg) cells in the periphery and skin of dermatitis-induced mice, and increased TGF-β expression, supporting their immunoregulatory phenotype, whereas, inhibition of T cell specific Hh-mediated transcription, resulted in impaired Treg function, which permitted progression of skin inflammation.
2021-07-14 | GSE117338 | GEO
Project description:Epithelial Hedgehog (Hh) ligands regulate several aspects of fetal intestinal organogenesis and emerging data implicate the Hh pathway in inflammatory signaling in adult colon. We investigated the effects of chronic Hh inhibition in vivo and profiled molecular pathways acutely modulated by Hh signaling in the intestinal mesenchyme. Experiment Overall Design: E18.5 intestinal mesenchyme was isolated and cultured. Mesenchyme was treated with Sonic (Shh) or Indian (Ihh) hedgehog ligand or Vehicle (control) acutely to identify targets regulated by Hh signaling in intestinal mesenchyme.
2009-11-10 | E-GEOD-17840 | biostudies-arrayexpress
Project description:Sivakumar2011 - Hedgehog Signaling Pathway
This is the current model for the Hedgehog signaling pathway. The best data for mechanism of signaling has been worked out in Drosophila, so this model is based largely on Drosophila data. Hedgehog target genes vary from tissue to tissue, so the identities of individual target genes have not been listed. The main difference between the Drosophila and mammalian Hedgehog signaling pathways is the fact that there are three mammalian homologs of Cubitus interruptus, Gli1 Gli2 and Gli3. Some or all of the mammalian homologs may be proteolytically processed, but the data are controversial. There are two mammalian Ptc genes and three mammalian Hedgehog genes as well. The pathway for Sonic Hedgehog appears to be most similar to the Drosophila hedgehog pathway.
References:
Hedgehog signaling in animal development: paradigms and principles.
Sonic hedgehog in the nervous system: functions, modifications and mechanisms.
Hedgehog signal transduction: recent findings.
Hedgehog signaling: Costal-2 bridges the transduction gap.
This model is described in the article:
A systems biology approach to model neural stem cell regulation by notch, shh, wnt, and EGF signaling pathways.
Sivakumar KC, Dhanesh SB, Shobana S, James J, Mundayoor S.
Omics: a Journal of Integrative Biology. 2011; 15(10):729-737
Abstract:
The Notch, Sonic Hedgehog (Shh), Wnt, and EGF pathways have long been known to influence cell fate specification in the developing nervous system. Here we attempted to evaluate the contemporary knowledge about neural stem cell differentiation promoted by various drug-based regulations through a systems biology approach. Our model showed the phenomenon of DAPT-mediated antagonism of Enhancer of split [E(spl)] genes and enhancement of Shh target genes by a SAG agonist that were effectively demonstrated computationally and were consistent with experimental studies. However, in the case of model simulation of Wnt and EGF pathways, the model network did not supply any concurrent results with experimental data despite the fact that drugs were added at the appropriate positions. This paves insight into the potential of crosstalks between pathways considered in our study. Therefore, we manually developed a map of signaling crosstalk, which included the species connected by representatives from Notch, Shh, Wnt, and EGF pathways and highlighted the regulation of a single target gene, Hes-1, based on drug-induced simulations. These simulations provided results that matched with experimental studies. Therefore, these signaling crosstalk models complement as a tool toward the discovery of novel regulatory processes involved in neural stem cell maintenance, proliferation, and differentiation during mammalian central nervous system development. To our knowledge, this is the first report of a simple crosstalk map that highlights the differential regulation of neural stem cell differentiation and underscores the flow of positive and negative regulatory signals modulated by drugs.
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2024-09-02 | BIOMD0000000395 | BioModels
Project description:Sonic hedgehog (Shh) signals via Gli transcription factors to direct digit number and identity in the vertebrate limb. We have characterized the Gli-dependent cis-regulatory network through a combination of whole genome ChIP-on-chip and transcriptional profiling of the developing mouse limb. These analyses identified approximately 5,000 high quality Gli3 binding sites, including all known Gli-dependent enhancers. Discrete binding regions exhibit a higher-order clustering, highlighting the complexity of cis-regulatory interactions. Further, Gli3 binds inertly to previously identified neural-specific Gli enhancers, demonstrating the accessibility of their cis-regulatory elements. Intersection of DNA binding data with gene expression profiles predicted 205 putative limb target genes. The supplementary bed file contains all 5,274 high quality binding Gli3 binding sites reported in the paper.
2008-09-15 | GSE11062 | GEO