Role of GLI-signaling in the postnatal cardiomyocyte development
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE201589 | GEO | 2024/11/27
REPOSITORIES: GEO
Dataset's files
Items per page: 5 1 - 5 of 5 |
Similar Datasets
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: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:The goal of this study is to analyze changes in gene expression produced in posterior midguts after knocking down Gli in enterocytes (EC) during 9 days. Gli was depleted from ECs using a drug-inducible version of the binary GAL4-UAS system in combination with UAS-GLI-RNAi. Targeted gene expression using the 5966GS-GAL4 driver is observed in adult ECs when flies are fed the progesterone analog RU486 (RU+); addition of ethanol is used as a control (RU-), providing cohorts of isogenic individuals with or without induction of the Gli-RNAi transgene.
2016-12-18 | GSE74168 | GEO
Project description:Decades of progress in developmental cardiology has advanced our understanding of the early aspects of heart development, including cardiomyocyte (CM) differentiation. However, control of CM maturation which is subsequently required to generate adult myocytes, remains elusive. Here, we analyzed over 200 microarray datasets from early embryonic to adult hearts and identified a large number of genes whose expression shifts gradually and continuously during maturation. We generated an atlas of integrated gene expression, biological pathways, transcriptional regulators, and gene regulatory networks (GRNs), which show discrete sets of key transcriptional regulators and pathways activated or suppressed during CM maturation. We developed a GRN-based program named MatStatCM that indexes CM maturation status. MatStatCM reveals that pluripotent stem cell-derived CMs mature early in culture, but are arrested at the late embryonic stage with aberrant regulation of key transcription factors. Our study provides a foundation for understanding CM maturation.
2015-11-16 | GSE73233 | GEO
Project description:Proper Hedgehog (HH) signaling is essential for normal embryonic and postnatal development, while de-regulated HH signaling drives numerous pediatric and adult cancers. In pancreatic cancer, paracrine HH signaling from tumor cells to fibroblasts contributes to tumor progression. However, the role of HH signaling in pancreatic cancer remains controversial, with both tumor-promoting and tumor-restraining functions reported. Notably, the GLI family of transcription factors (GLI1, GLI2, GLI3), key downstream effectors of HH signaling, remain poorly understood in pancreatic cancer. In this study we investigated the individual and combined roles of GLI1-3 in pancreatic cancer progression. Inducible, fibroblast-specific deletion of Gli2 and Gli3 in a mouse model of pancreatic cancer progression reduces collagen deposition and decreases immunosuppressive myeloid cell infiltration. Further, Gli2 and Gli3 deletion leads to an increase in T cells during PanIN stages and an increase in NK cells in implanted tumors, which in turn suppresses tumor growth. Surprisingly, combined loss of all three Glis leads to a widespread loss of acinar cells, an increase in macrophage infiltration, and an increase in tumor growth. Together, these data indicate that a baseline level of Gli is necessary to maintain proper balance of cell types in the pancreas, and the coordinated activity of GLI1-3 directs the fibroinflammatory response in pancreatic cancer.
2022-07-05 | GSE185748 | GEO
Project description:In studies investigating Sonic hedgehog (Shh) mediated patterning of the ventral neural tube, a process where Shh acts as a morphogen, we have investigated the transcriptional network underlying neural tube specification. Adopting an ES-cell based Shh neuronal specification assay (embryoid body; EBs) and a FLAG-tagged Gli protein (a transcriptional effector of the Shh pathway), we identified a number of direct targets of Gli action using Chromatin Immunoprecipitation (ChIP). These results will provide a first survey of the genome level response to this critical signaling input in vertebrate patterning Keywords: ChIP-chip, Gli transcription factors, Gli1, neural specification, mouse
2007-04-20 | GSE5683 | GEO
Project description:Despite significant progress in therapy, melanoma is still the most lethal form of skin cancer, with a rising incidence worldwide. Little is known about the impact of deregulated Hedgehog-GLI (HH-GLI) signalling pathway in the progression of this disease. Based on previous research, we hypothesized that in melanoma activation of HH-GLI signaling pathway is non- canonical due to its crosstalk with MAPK signaling pathway, which is the most deregulated pathway in melanoma. In order to investigate the link between the two pathways and to find novel GLI transcriptional targets that could be considered for potential combination therapy, we performed RNA sequencing on three melanoma cell lines with overexpressed GLI1, GLI2 and GLI3 and combined them with results of ChIP sequencing on endogenous GLI1, GLI2 and GLI3 proteins on the same cell lines. RNA-seq revealed a total of 808 DEGs for GLI1, 941 DEGs for GLI2 and 58 DEGs for GLI3. ChIP-seq identified 527 genes that contained GLI1 binding sites in their promoters, 1103 for GLI2 and 553 for GLI3. After combining these results, 21 targets were selected for validation by qPCR. Fifteen of these targets were validated in the tested cell lines, 6 of which were detected by both RNA-seq and ChIP-seq.
2023-01-01 | E-MTAB-11936 | biostudies-arrayexpress
Project description:Contrary to adult mammals, zebrafish are able to regenerate their heart after cardiac injury. This regenerative response relies, in part, on the endogenous ability of cardiomyocytes (CMs) to dedifferentiate and proliferate to replenish the lost muscle. However, CM heterogeneity and population dynamics during development and regeneration remain poorly understood. Through comparative transcriptomic analyses of the developing and adult zebrafish heart, we identified tnnc2 and tnni4b.3 expression as markers for CMs at early and late developmental stages, respectively. Using newly developed reporter lines for these genes, we investigated their expression dynamics during development and regeneration, and observed interesting expression patterns. tnnc2 reporter lines label most CMs at embryonic stages, and this labeling declines rapidly during larval stages; in adult hearts expression is only detectable in a subset of CMs. Conversely, expression of a tnni4b.3 reporter is initially visible in outer curvature CMs at larval stages, and it is subsequently present in a vast majority of the CMs in adult hearts. Interestingly, we find that the adult CMs labeled by the embryonic reporter display higher levels of Tg(tp1:EGFP) expression, which indicates active Notch signaling. To further characterize this CM population, we performed transcriptomic analysis and found that it expresses genes encoding components of the Notch signaling pathway as well as markers of immature CMs. Moreover, during heart regeneration, proliferating CMs in the injured area activate the embryonic CM reporter. Overall, our findings provide further evidence of cardiomyocyte heterogeneity in the adult zebrafish heart.
2021-05-03 | GSE157662 | GEO
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:Mammalian hearts had the capability to regenerate cardiomyocyte and completely recover after heart injury within a limited time window after birth. It has been shown that sphingosine 1-phospahte receptor 1 (S1pr1) was highly expressed in cardiomyocytes and played an important role in heart development and pathological cardiac remodeling. Herein, we aim to investigate the role of CM-S1pr1 for cardiac regeneration and tissue repair after heart injury. We generated cardiomyocyte (CM)-specific S1pr1 knock-out mice and showed that CM-specific S1pr1 loss-of-function significantly severely reduced cardiomyocyte proliferation and heart regeneration in neonatal mice after both apex resection and myocardial infarction, whereas S1pr1 gain-of-function by AAV9-mediated CM-specific overexpression of S1pr1 significantly boosted cardiac regeneration and improved cardiac functions after heart injuries. We next identified that S1pr1 activated AKT/mTOR/CyclinD1 and Bcl-2 signaling pathways, and thus promoted cardiomyocyte proliferation and inhibited CM apoptosis, respectively.Of note, we applied CM-targeted gene therapy by AAV9-cTNT to specifically overexpress S1pr1 in cardiomyocytes and achieved an efficient S1pr1 overexpression in CMs in vivo. This CM-targeted strategy to overexpress S1pr1 significantly enhanced cardiac regeneration and improved cardiac functions after myocardial infarction in an adult mouse model, suggesting a potential strategy to boost adult cardiac regeneration in vivo.
2024-08-01 | GSE241722 | GEO