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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Extremities / embryology*
  • Female
  • Gene Expression Regulation, Developmental*
  • 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
  • Nuclear Matrix / genetics
  • Nuclear Matrix / metabolism
  • Point Mutation
  • Polydactyly / embryology
  • Polydactyly / genetics*
  • Polydactyly / metabolism
  • Protein Binding
  • Protein Transport


  • Hedgehog Proteins
  • Heterogeneous-Nuclear Ribonucleoprotein U
  • Shh protein, mouse