HnRNP U mediates the long-range regulation of Shh expression during limb development

Transcriptional modulation may be mediated by cis-regulatory elements distant from their target genes. Mutations in a conserved locus about 1 Mb upstream of the Shh coding region often affect Shh expression and are associated with preaxial polydactyly (PPD) defects. To understand the molecular mecha...

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Bibliographic Details
Published in:Human molecular genetics 2009-08, Vol.18 (16), p.3090-3097
Main Authors: Zhao, Jing, Ding, Jun, Li, Yingqian, Ren, Kaiqun, Sha, Jiahao, Zhu, Minsheng, Gao, Xiang
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Extremities - embryology
Female
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation, Developmental
Genetics of eukaryotes. Biological and molecular evolution
Hedgehog Proteins - genetics
Hedgehog Proteins - metabolism
Heterogeneous-Nuclear Ribonucleoprotein U - genetics
Heterogeneous-Nuclear Ribonucleoprotein U - metabolism
Humans
Male
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Molecular and cellular biology
Nuclear Matrix - genetics
Nuclear Matrix - metabolism
Point Mutation
Polydactyly - embryology
Polydactyly - genetics
Polydactyly - metabolism
Protein Binding
Protein Transport
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Summary:Transcriptional modulation may be mediated by cis-regulatory elements distant from their target genes. Mutations in a conserved locus about 1 Mb upstream of the Shh coding region often affect Shh expression and are associated with preaxial polydactyly (PPD) defects. To understand the molecular mechanism, we analyzed a novel mouse PPD model with a T-to-A point mutation in this distant locus. A core element of mutation (CEM) with putative enhancer activity was identified by promoter activity assay and shown to contain a matrix attachment region. HnRNP U preferentially bound to the mutant but not the wild-type CEM. Interestingly, HnRNP U also bound to the 5′-UTR of the Shh gene, which was not located in the nuclear matrix in wild-type embryonic cells, as indicated by chromatin immunoprecipitation. We propose that the 5′-UTR of Shh was pulled into the nuclear matrix by HnRNP U when the CEM was mutated, and consequently affected Shh expression. Therefore, distant cis-elements may modulate gene expression by altering HnRNP U's affinity for certain mediator proteins and nuclear relocation.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddp250