Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

ChIP-seq analysis of Gli1 and Sox2 input to neural progenitor program and integration with actve histone marks

ABSTRACT: In the vertebrate neural tube, regional Sonic hedgehog (Shh) signaling invokes a time- and concentration-dependent induction of six different cell populations mediated through Gli transcriptional regulators. Elsewhere in the embryo, Shh/Gli responses invoke different tissue appropriate regulatory programs. To elucidate Shh/Gli regulation of neural fate sepcification, we performed Gli1 ChIP-Seq analysis. We further analyzed two transcription factors whose motifs were enriched in Gli1 ChIP data (Sox2 and Foxa2). Two active histone marks (H3K4me2 and H3K27ac) were additionally analyzed to study activity status of Shh-responsive cis-elements. Active enhancer histone marks and transcription factor binding patterns were obtained from neuralized emrbyoid bodies. Biological replicates were performed for Gli1 and mock FLAG chips. Histone profiling for enhancer marks were taken from time course experiment performed in parallel.

ORGANISM(S): Mus musculus

SUBMITTER: Kevin Peterson

PROVIDER: E-GEOD-42132 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Neural-specific Sox2 input and differential Gli-binding affinity provide context and positional information in Shh-directed neural patterning.

Peterson Kevin A KA Nishi Yuichi Y Ma Wenxiu W Vedenko Anastasia A Shokri Leila L Zhang Xiaoxiao X McFarlane Matthew M Baizabal José-Manuel JM Junker Jan Philipp JP van Oudenaarden Alexander A Mikkelsen Tarjei T Bernstein Bradley E BE Bailey Timothy L TL Bulyk Martha L ML Wong Wing H WH McMahon Andrew P AP

Genes & development 20121201 24

In the vertebrate neural tube, regional Sonic hedgehog (Shh) signaling invokes a time- and concentration-dependent induction of six different cell populations mediated through Gli transcriptional regulators. Elsewhere in the embryo, Shh/Gli responses invoke different tissue-appropriate regulatory programs. A genome-scale analysis of DNA binding by Gli1 and Sox2, a pan-neural determinant, identified a set of shared regulatory regions associated with key factors central to cell fate determination ...[more]

PMID: 23249739

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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.

Dataset Information

ChIP-seq analysis of Gli1 and Sox2 input to neural progenitor program and integration with actve histone marks

Publications

Neural-specific Sox2 input and differential Gli-binding affinity provide context and positional information in Shh-directed neural patterning.

Similar Datasets

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