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Hum Mol Genet. 2009 Aug 15;18(16):3090-7. doi: 10.1093/hmg/ddp250. Epub 2009 May 28.

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

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  • 1MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Medical School of Nanjing University, 12 Xuefu Road, Pukou District, Nanjing 210063, PR China.

Abstract

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.

PMID:
19477957
DOI:
10.1093/hmg/ddp250
[PubMed - indexed for MEDLINE]
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