GLI2-mediated mesenchymal Hh signaling induces stem cell niche signals in intestinal development and tumorigenesis
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PROVIDER: PRJNA404062 | ENA |
REPOSITORIES: ENA
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Project description:Mesenchymal-epithelial interactions play a critical role in organ development, stem cells and disease. During intestinal development, pseudostratified epithelia undergo dramatic morphogenesis called villification, to form finger-like projections, in which mesenchymal cell clustering and muscle layers play a key role. In the adult, the gut mesenchyme is proposed as a key intestinal stem cell niche providing essential niche signals such as Wnt ligands, while the TGF beta signaling mediated gut stromal program is critical for cancer progression. However, how these signals are produced is currently unknown. In the gut, Hedgehog (Hh) signaling acts strictly in a paracrine manner: Hh ligands are expressed in the epithelium and activate signaling exclusively in the mesenchyme. Notably, Hh signaling is not only essential for mesenchymal clustering and muscle differentiation, it is also involved in intestinal tumorigenesis. To investigate Hh mediated mechanisms, we analyzed mice deleted for key Hh negative regulators, Sufu and/or Spop in the gut mesenchyme, and demonstrated their dosage dependent role in the negative regulation of Hh signaling. Although these mutants exhibit abnormal mesenchymal cell growth and functionally defective muscle layers, villification is completed with proper mesenchymal clustering, implying a permissive role for Hh signaling. These mesenchymal defects are partially rescued by Gli2 reduction, demonstrating the significance of its transcriptional regulation. Surprisingly, in contrast to its known inhibitory role in epithelial proliferation, abnormal Hh activation in the gut mesenchyme leads to increased epithelial proliferation. Corroborating this data, Sufu reduction is sufficient to promote intestinal tumorigenesis, while Gli2 heterozygosity suppresses it. To define GLI2-mediated downstream mechanisms, we mapped its binding sites and analyzed gene expression genome-wide, identifying one of the most robust Hh direct targetome data sets ever reported. This work reveals the GLI2 transcriptional regulation of Wnt and TGF beta pathways in stem cell proliferation and muscle differentiation, providing mechanistic insight into the intestinal stem cell niche in development and tumorigenesis.
2019-06-04 | GSE103690 | GEO
Project description:Mesenchymal-epithelial interactions play a critical role in organ development, stem cells and disease. During intestinal development, pseudostratified epithelia undergo dramatic morphogenesis called villification, to form finger-like projections, in which mesenchymal cell clustering and muscle layers play a key role. In the adult, the gut mesenchyme is proposed as a key intestinal stem cell niche providing essential niche signals such as Wnt ligands, while the TGF beta signaling mediated gut stromal program is critical for cancer progression. However, how these signals are produced is currently unknown. In the gut, Hedgehog (Hh) signaling acts strictly in a paracrine manner: Hh ligands are expressed in the epithelium and activate signaling exclusively in the mesenchyme. Notably, Hh signaling is not only essential for mesenchymal clustering and muscle differentiation, it is also involved in intestinal tumorigenesis. To investigate Hh mediated mechanisms, we analyzed mice deleted for key Hh negative regulators, Sufu and/or Spop in the gut mesenchyme, and demonstrated their dosage dependent role in the negative regulation of Hh signaling. Although these mutants exhibit abnormal mesenchymal cell growth and functionally defective muscle layers, villification is completed with proper mesenchymal clustering, implying a permissive role for Hh signaling. These mesenchymal defects are partially rescued by Gli2 reduction, demonstrating the significance of its transcriptional regulation. Surprisingly, in contrast to its known inhibitory role in epithelial proliferation, abnormal Hh activation in the gut mesenchyme leads to increased epithelial proliferation. Corroborating this data, Sufu reduction is sufficient to promote intestinal tumorigenesis, while Gli2 heterozygosity suppresses it. To define GLI2-mediated downstream mechanisms, we mapped its binding sites and analyzed gene expression genome-wide, identifying one of the most robust Hh direct targetome data sets ever reported. This work reveals the GLI2 transcriptional regulation of Wnt and TGF beta pathways in stem cell proliferation and muscle differentiation, providing mechanistic insight into the intestinal stem cell niche in development and tumorigenesis.
2019-06-04 | GSE103683 | GEO
Project description:Purpose: Human Embryonic Stem Cell (hESC)-derived insulin-producing beta cells offer a promising cell-based therapy for diabetes. However, efficient hESC to beta cell differentiation has proven difficult, possibly due to the lack of cross-talk with the appropriate mesenchymal niche. To define organ-specific niche signals, we isolated pancreatic and gastrointestinal stromal cells and analyzed their transcriptomes during development. Methods: mRNA profiles from E13.5 mice were generated from mesenchymal cells dissected from wild-type (WT) intestine, stomach, pancreas and mutant Sufu-/- Spop -/- pancreatic mesenchyme, in duplicate, by illumina HiSeq 2500. Reads were aligned to the mm10 assembly and unambiguously mapping reads were analyzed at the gene level for differential expression between tissue types alignment using STAR and differential analysis using DESeq2. Results: Using our workflow, we mapped about 30 million reads per sample to mm10. Differential expression (DE) analysis identified over 900 significantly differentially expressed genes between WT pancreatic mesenchyme and gastrointestinal mesenchymes, and over 1100 genes differentially expressed between WT and mutant pancreatic mesenchyme. Our findings reveal the importance of tightly-regulated Hh signaling in the pancreatic mesenchyme. In vivo inactivation of mesenchymal Hh signaling leads to annular pancreas, and stroma-specific activation of Hh signaling via loss of Hh regulators, Sufu and Spop, impairs pancreatic growth and beta cell genesis. Genetic rescue and transcriptome analyses show that these Sufu and Spop knockout defects occur through GLI2-mediated activation of gastrointestinal stromal signals such as Wnt ligands. Importantly, inhibition of Wnt signaling in organoid and hESC cultures significantly promotes insulin-producing cell generation, revealing the requirement for organ-specific regulation of stromal niche signals.
2019-09-12 | GSE123136 | GEO
Project description:We demonstrate the conserved Hh-GLI2-mediated chromatin and transcriptional regulation of both stomach and intestinal stromal stem cell niche signals. Analyses of H3K27ac marks demonstrate GLI2-mediated transcription regulation of stem cell niche signals such as Wnt ligand genes, through enhancers conserved between the stomach and intestine.
2019-12-14 | GSE114450 | GEO
Project description:We demonstrate the conserved Hh-GLI2-mediated chromatin and transcriptional regulation of both stomach and intestinal stromal stem cell niche signals. Analyses of H3K27ac marks demonstrate GLI2-mediated transcription regulation of stem cell niche signals such as Wnt ligand genes, through enhancers conserved between the stomach and intestine.
2019-12-14 | GSE114449 | GEO
Project description:The capacity of stem cells to maintain and regenerate organs is critically dependent on the niche, a complex signaling microenvironment that sustains and regulates stem cell activity. Niche function in the mammary gland must integrate local homeostatic activities with hormonally regulated events, such as pregnancy or the onset of puberty. In the human disorder CPHD (combined pituitary hormone deficiency) breast growth defects at puberty are associated with mutations disrupting the transcription factor, GLI2. Here we find that Gli2 functions in mouse mammary stromal cells to shape a niche signaling program that sustains mammary epithelial stem cells. Ablation of Gli2 in stromal cells thus leads to a disorganized mammary gland, associated with collapse of the niche signaling environment, with a five-fold decrease in functional mammary stem cell activity, and with attenuated response to the mammatrophic hormones estrogen and growth hormone. Consistent with a niche defect, aspects of Gli2-deficient mammary gland architecture can be rescued by local supplementation with IGF and WNT protein signals. Our findings thus identify GLI2 as a critical coordinator of local and hormonal influences on the niche signaling program, and suggest that mammary pathogenesis in CPHD patients results from dysfunction of the mammary epithelial stem cell niche. We used microarrays to identify gene expression signatures associated with stromal Gli2 expression
2015-03-13 | GSE66820 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-06-04 | GSE103691 | GEO
Project description:Aberrations in the Hedgehog (Hh) pathway are known to related to several malignancies. However, little is known about the function of GLI2, a transcription factor in the Hh pathway, in osteosarcoma. Osteosarcoma is the most frequent primary bone sarcoma in children and adolescents. Despite survival rates of osteosarcoma patients have increased, the prognosis of patients with metastasis remains poor. Therefore, the development of novel therapeutic strategies for osteosarcoma patients is development of novel therapeutic strategies for osteosarcoma patients is urgently needed. Aberrations in the Hedgehog (Hh) pathway are known to related to several malignancies. However, little is known about the function of GLI2, a transcription factor in the Hh pathway, in osteosarcoma. Our findings revealed that GLI2 was overexpressed in osteosarcoma tissues. Additionally, GLI2 is involved in the metastasis of osteosarcoma cells through the regulation of ribosomal protein S3 expression. Furthermore, we showed that arsenic trioxide (ATO) suppressed the invasion and lung metastasis of osteosarcoma cells by the inhibition of GLI transcription. Consequently, these finding reveal a novel function of GLI2 in the metastasis of osteosarcoma and that ATO may be a new therapeutic agentay be a new therapeutic agent. We revealed that a novel function of GLI2 in the metastasis of osteosarcoma and that ATO may be a new therapeutic agent for preventing osteosarcoma metastasis. Negative siRNA(U-2OS) and GLI2 siRNA(U-2OS)
2012-12-14 | E-GEOD-42903 | biostudies-arrayexpress
Project description:GLI2-mediated mesenchymal Hh signaling induces stem cell niche signals in intestinal development and tumorigenesis [RNASeq]
| PRJNA404049 | ENA
Project description:GLI2-mediated mesenchymal Hh signaling induces stem cell niche signals in intestinal development and tumorigenesis [ChIPSeq]
| PRJNA404066 | ENA