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Regulation of tyrosine hydroxylase transcription by hnRNP K and DNA secondary structure

Author

Listed:
  • Kasturi Banerjee

    (Burke Medical Research Institute)

  • Meng Wang

    (Burke Medical Research Institute)

  • Elizabeth Cai

    (Burke Medical Research Institute)

  • Nana Fujiwara

    (Burke Medical Research Institute)

  • Harriet Baker

    (Burke Medical Research Institute
    Brain and Mind Research Institute, Weill Cornell Medical College)

  • John W. Cave

    (Burke Medical Research Institute
    Brain and Mind Research Institute, Weill Cornell Medical College)

Abstract

Regulation of tyrosine hydroxylase gene (Th) transcription is critical for specifying and maintaining the dopaminergic neuronal phenotype. Here we define a molecular regulatory mechanism for Th transcription conserved in tetrapod vertebrates. We show that heterogeneous nuclear ribonucleoprotein (hnRNP) K is a transactivator of Th transcription. It binds to previously unreported and evolutionarily conserved G:C-rich regions in the Th proximal promoter. hnRNP K directly binds to C-rich single-stranded DNA within these conserved regions and also associates with double-stranded sequences when proteins, such as CRE-binding protein, are bound to an adjacent cis-regulatory element. The single DNA strands within the conserved G:C-rich regions adopt either G-quadruplex or i-motif secondary structures. We also show that small molecule-mediated stabilization of these secondary structures represses Th promoter activity. These data suggest that these secondary structures are targets for pharmacological modulation of the dopaminergic phenotype.

Suggested Citation

  • Kasturi Banerjee & Meng Wang & Elizabeth Cai & Nana Fujiwara & Harriet Baker & John W. Cave, 2014. "Regulation of tyrosine hydroxylase transcription by hnRNP K and DNA secondary structure," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6769
    DOI: 10.1038/ncomms6769
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