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Identification of genetic targets of Hh signaling in Drosophila

ABSTRACT: Paracrine Hedgehog (Hh) signaling regulates growth and patterning in many Drosophila organs. We mapped chromatin binding sites for Cubitus interruptus (Ci), the transcription factor that mediates outputs of Hh signal transduction, and we analyzed transcription profiles of control and mutant embryos to identify genes that are regulated by Hh. Putative targets we identified include several Hh pathway components, most previously identified targets, and many targets that are novel. Analysis of expression patterns of pathway components and target genes gave evidence of autocrine Hh signaling in the optic primordium of the embryo. And, every Hh target we analyzed that is not a pathway component appeared to be regulated by Hh in a tissue-specific manner. We present evidence that Hh-dependent tissue specificity is dependent upon transcription factors that are Hh-independent, suggesting that “pre-patterns” of transcription factors partner with Ci to make Hh-dependent gene expression position-specific. Analysis of the expression profiles of loss of function mutantations in core components of the Hh signaling pathway. A total of 14 samples were analysed consisting of comparisons of hh-, ci-, smo-, ptc-, and Cim1-m4 (Activator) mis-expression embryos compared to wt sibling embryos.

ORGANISM(S): Drosophila melanogaster

SUBMITTER: Brian Biehs

PROVIDER: E-GEOD-24028 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Mapping the binding regions of the cubitus interruptus (Ci) activator form

Project description:Paracrine Hedgehog (Hh) signaling regulates growth and patterning in many Drosophila organs. We mapped chromatin binding sites for Cubitus interruptus (Ci), the transcription factor that mediates outputs of Hh signal transduction, and we analyzed transcription profiles of control and mutant embryos to identify genes that are regulated by Hh. Putative targets we identified include several Hh pathway components, most previously identified targets, and many targets that are novel. Analysis of expression patterns of pathway components and target genes gave evidence of autocrine Hh signaling in the optic primordium of the embryo. And, every Hh target we analyzed that is not a pathway component appeared to be regulated by Hh in a tissue-specific manner. We present evidence that Hh-dependent tissue specificity is dependent upon transcription factors that are Hh-independent, suggesting that “pre-patterns” of transcription factors partner with Ci to make Hh-dependent gene expression position-specific. We utilized the DamID method to identify regions of CiAct methylated genomic DNA in stage 10-11 Drosophila embryos. Comparison of DamCiAct directed methylation vs. Dam Alone background methylation using 3 replicate experiments.

2010-11-03 | E-GEOD-23999 | biostudies-arrayexpress

Mapping the binding regions of the cubitus interruptus (Ci) repressor form

Project description:Paracrine Hedgehog (Hh) signaling regulates growth and patterning in many Drosophila organs. We mapped chromatin binding sites for Cubitus interruptus (Ci), the transcription factor that mediates outputs of Hh signal transduction, and we analyzed transcription profiles of control and mutant embryos to identify genes that are regulated by Hh. Putative targets we identified include several Hh pathway components, most previously identified targets, and many targets that are novel. Analysis of expression patterns of pathway components and target genes gave evidence of autocrine Hh signaling in the optic primordium of the embryo. And, every Hh target we analyzed that is not a pathway component appeared to be regulated by Hh in a tissue-specific manner. We present evidence that Hh-dependent tissue specificity is dependent upon transcription factors that are Hh-independent, suggesting that “pre-patterns” of transcription factors partner with Ci to make Hh-dependent gene expression position-specific. We utilized the DamID method to identify regions of CiRep methylated genomic DNA in stage 10-11 Drosophila embryos. Comparison of DamCiRep directed methylation vs. Dam Alone background methylation using 3 replicate experiments.

2010-11-03 | E-GEOD-24024 | biostudies-arrayexpress

Identification of genetic targets of Hh signaling in Drosophila

2010-11-03 | GSE24028 | GEO

Mapping the binding regions of the cubitus interruptus (Ci) repressor form

Project description:Paracrine Hedgehog (Hh) signaling regulates growth and patterning in many Drosophila organs. We mapped chromatin binding sites for Cubitus interruptus (Ci), the transcription factor that mediates outputs of Hh signal transduction, and we analyzed transcription profiles of control and mutant embryos to identify genes that are regulated by Hh. Putative targets we identified include several Hh pathway components, most previously identified targets, and many targets that are novel. Analysis of expression patterns of pathway components and target genes gave evidence of autocrine Hh signaling in the optic primordium of the embryo. And, every Hh target we analyzed that is not a pathway component appeared to be regulated by Hh in a tissue-specific manner. We present evidence that Hh-dependent tissue specificity is dependent upon transcription factors that are Hh-independent, suggesting that “pre-patterns” of transcription factors partner with Ci to make Hh-dependent gene expression position-specific. We utilized the DamID method to identify regions of CiRep methylated genomic DNA in stage 10-11 Drosophila embryos.

2010-11-03 | GSE24024 | GEO

Mapping the binding regions of the cubitus interruptus (Ci) activator form

2010-11-03 | GSE23999 | GEO

Hedgehog targets in the Drosophila embryo and the mechanisms that generate tissue-specific outputs of Hedgehog signaling

Project description:This SuperSeries is composed of the following subset Series: GSE23999: Mapping the binding regions of the cubitus interruptus (Ci) activator form GSE24024: Mapping the binding regions of the cubitus interruptus (Ci) repressor form GSE24028: Identification of genetic targets of Hh signaling in Drosophila Refer to individual Series

2010-11-03 | E-GEOD-24055 | biostudies-arrayexpress

The stem cell-associated transcription co-factor, ZNF521, interacts with GLI1 and GLI2 and enhances the activity of the Sonic hedgehog pathway

Project description:ZNF521 is a transcription co-factor with recognized regulatory functions in haematopoietic, osteo-adipogenic and neural progenitor cells. Among its diverse activities, ZNF521 has been implicated in the regulation of medulloblastoma (MB) cells, where the Hedgehog (HH) pathway, has a key role in the development of normal cerebellum and of a substantial fraction of MBs. Here a functional cross-talk is shown for ZNF521 with the HH pathway, where it interacts with GLI1 and GLI2, the major HH transcriptional effectors and enhances the activity of HH signalling. In particular, ZNF521 cooperates with GLI1 and GLI2 in the transcriptional activation of GLI (glioma-associated transcription factor)-responsive promoters. This synergism is dependent on the presence of the N-terminal, NuRD-binding motif in ZNF521, and is sensitive to HDAC (histone deacetylase) and GLI inhibitors. Taken together, these results highlight the role of ZNF521, and its interaction with the NuRD complex, in determining the HH response at the level of transcription. This may be of particular relevance in HH-driven diseases, especially regarding the MBs belonging to the SHH (sonic HH) subgroup where a high expression of ZNF521 is correlated with that of HH pathway components.

2020-10-03 | GSE158925 | GEO

Anti-ZFX ChIP-seq in a human medulloblastoma cell line

Project description:The Hedgehog (Hh) signaling pathway regulates normal development and cell proliferation, whereas its aberrant activation causes tumor formation. Hh-induced tumors can arise from different tissues and can be indolent or highly aggressive, such as basal cell carcinoma (BCC) of the skin and neural progenitor-derived medulloblastoma (MB), respectively. Little is known about cell-intrinsic factors that control the development of such diverse Hh-dependent tumors. Transcription factor Zfx is required for the self-renewal of several stem cell types, whereas its role in malignant transformation remains controversial. We found that the deletion of Zfx prevented BCC formation and significantly delayed MB development caused by Hh activation in vivo. In contrast, Zfx was dispensable for the development of Hh-independent brain tumor glioblastoma. We used genome-wide expression and chromatin binding analysis in a human MB cell line to identify direct, evolutionarily conserved targets of Zfx. These targets included the Hh signal transducer Smoothened (Smo), suggesting that Zfx may directly control Hh pathway activation in tumors. Two additional targets of Zfx, Dis3L and Ube2j1, were also required for the growth of MB cells in vitro. These results identify a common cell-intrinsic regulator of diverse Hh-induced tumors, and suggest Zfx and Zfx-controlled genes as possible therapeutic targets in these malignancies.

2014-12-31 | GSE45394 | GEO

Effect of lentiviral-based shRNA-mediated knockdown of ZFX on the human medulloblastoma (MB) cell-line DAOY

2014-12-31 | GSE45265 | GEO

Dachshund ChIP-seq in Drosophila Melanogaster 3rd instar imaginal eye discs

Project description:The patterning of Drosophila retina occurs both very fast and with high precision. This process is driven by the dynamic changes in signalling activity of the conserved Hedgehog (Hh) pathway, which coordinates cell fate determination, cell cycle and tissue morphogenesis. Here we show that during Drosophila retinogenesis, the retinal determination gene dachshund (dac) is not only a target of the Hh signaling pathway, but is also a modulator of its activity. Using developmental genetics techniques, we demonstrate that dac enhances Hh signaling by promoting the accumulation of the Gli transcription factor Cubitus interruptus (Ci) parallel to or downstream of fused. In the absence of dac, all Hh-mediated events associated to the morphogenetic furrow are delayed. One of the consequences is that, posterior to the furrow, dac- cells cannot activate a Roadkill-Cullin3 negative feedback loop that attenuates Hh signaling and which is necessary for retinal cells to continue normal differentiation. Therefore, dac is part of an essential positive feedback loop in the Hh pathway, guaranteeing the speed and the accuracy of Drosophila retinogenesis.

2016-07-01 | GSE82151 | GEO

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