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A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb
- Source :
- Genes & Development. 22:2651-2663
- Publication Year :
- 2008
- Publisher :
- Cold Spring Harbor Laboratory, 2008.
-
Abstract
- Sonic hedgehog (Shh) signals via Gli transcription factors to direct digit number and identity in the vertebrate limb. We characterized the Gli-dependent cis-regulatory network through a combination of whole-genome chromatin immunoprecipitation (ChIP)-on-chip and transcriptional profiling of the developing mouse limb. These analyses identified ∼5000 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 from 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.
- Subjects :
- Chromatin Immunoprecipitation
animal structures
Kruppel-Like Transcription Factors
Gene regulatory network
Mice, Transgenic
Nerve Tissue Proteins
Biology
Models, Biological
Mice
Pregnancy
Zinc Finger Protein Gli3
GLI3
Basic Helix-Loop-Helix Transcription Factors
Genetics
Animals
Gene Regulatory Networks
Hedgehog Proteins
Sonic hedgehog
Enhancer
Transcription factor
Body Patterning
Binding Sites
Activator (genetics)
Genetic Complementation Test
Extremities
Genomics
Cell biology
Enhancer Elements, Genetic
embryonic structures
biology.protein
Cytokines
Intercellular Signaling Peptides and Proteins
Female
Positive Regulatory Domain I-Binding Factor 1
Chromatin immunoprecipitation
Research Paper
Signal Transduction
Transcription Factors
Developmental Biology
Morphogen
Subjects
Details
- ISSN :
- 15495477 and 08909369
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Genes & Development
- Accession number :
- edsair.doi.dedup.....f6aa7ce4e17afda6a3f8f198f59dc0a0