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XB-ART-1899
Dev Biol May 15, 2005; 281 (2): 210-26.

Phylogenetic footprinting and genome scanning identify vertebrate BMP response elements and new target genes.

von Bubnoff A , Peiffer DA , Blitz IL , Hayata T , Ogata S , Zeng Q , Trunnell M , Cho KW .


Abstract
The complex gene regulatory networks governed by growth factor signaling are still poorly understood. In order to accelerate the rate of progress in uncovering these networks, we explored the usefulness of interspecies sequence comparison (phylogenetic footprinting) to identify conserved growth factor response elements. The promoter regions of two direct target genes of Bone Morphogenetic Protein (BMP) signaling in Xenopus, Xvent2 and XId3, were compared with the corresponding human and/or mouse counterparts to identify conserved sequences. A comparison between the Xenopus and human Vent2 promoter sequences revealed a highly conserved 21 bp sequence that overlaps the previously reported Xvent2 BMP response element (BRE). Reporter gene assays using Xenopus animal pole ectodermal explants (animal caps) revealed that this conserved 21 bp BRE is both necessary and sufficient for BMP responsiveness. We combine the same phylogenetic footprinting approach with luciferase assays to identify a highly conserved 49 bp BMP responsive region in the Xenopus Id3 promoter. GFP reporters containing multimers of either the Xvent2 or XId3 BREs appear to recapitulate endogenous BMP signaling activity in transgenic Xenopus embryos. Comparison of the Xvent2 and the XId3 BRE revealed core sequence features that are both necessary and sufficient for BMP responsiveness: a Smad binding element (SBE) and a GC-rich element resembling an OAZ binding site. Based on these findings, we have implemented genome scanning to identify over 100 additional putative target genes containing 2 or more BRE-like sequences which are conserved between human and mouse. RT-PCR and in situ analyses revealed that this in silico approach can effectively be used to identify potential BMP target genes.

PubMed ID: 15893974
Article link: Dev Biol
Grant support: [+]
Genes referenced: aadat ammecr1 babam2 bmp2 bmp4 csnk2a1 dach1 dlx5 flrt3 fst hoxa13 id3 kansl2 kat8 limk2 lrch4 lrrn1 mef2a mpped2 olfm4 prkca prkd1 ptpn3 sall1 snrpe spdl1 stk24 stk3 tbx2 trps1 ventx2.2 wnt11 zeb2 znf423


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