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A Genome-Scale Analysis of the Cis-Regulatory Circuitry Underlying Hedgehog Mediated Patterning of the Mammalian Limb

ABSTRACT: 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. A subset of putative cis-regulatory regions were analyzed in transgenic embryos, establishing Blimp1 as a direct Gli target and identifying Gli-activator signaling in a direct, long-range regulation of the BMP antagonist Gremlin. In contrast, a long range silencer cassette downstream of Hand2 likely mediates Gli3 repression in the anterior limb. These studies provide the first comprehensive characterization of the transcriptional output of a Shh-patterning process in the mammalian embryo and a framework for elaborating regulatory networks in the developing limb. This SuperSeries is composed of the SubSeries listed below.

OTHER RELATED OMICS DATASETS IN: PRJNA108815PRJNA107069PRJNA108817

ORGANISM(S): Mus musculus

PROVIDER: GSE11077 | GEO | 2008/09/15

SECONDARY ACCESSION(S): PRJNA107069

REPOSITORIES: GEO

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Genome-Wide Gli3 Binding Sites in the E11.5 Mouse Limb Bud

2008-09-15 | GSE11062 | GEO

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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

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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.

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GLI3 binding regions in mouse embryonic forelimb buds

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