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

Kasturi Banerjee, Meng Wang, Elizabeth Cai, Nana Fujiwara, Harriet Baker and John W. Cave ()
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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
John W. Cave: Burke Medical Research Institute

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6769

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DOI: 10.1038/ncomms6769

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