A genome-scale analysis of the cis-regulatory circuitry underlying sonic hedgehog-mediated patterning of the mammalian limb

被引:231
作者
Vokes, Steven A. [1 ]
Ji, Hongkai [2 ,3 ]
Wong, Wing H. [3 ]
McMahon, Andrew P. [1 ,4 ]
机构
[1] Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA
[2] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA
[3] Stanford Univ, Dept Stat, Stanford, CA 94305 USA
[4] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA
关键词
sonic hedgehog; limb; morphogen; gli; cis-regulatory network;
D O I
10.1101/gad.1693008
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 similar to 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.
引用
收藏
页码:2651 / 2663
页数:13
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