title: Regulation of tyrosine hydroxylase transcription by hnRNP K and DNA secondary structure.
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.
authors.affiliation: Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York 10605, USA.
authors.forename: Kasturi
authors.initials: K
authors.lastname: Banerjee
authors.affiliation: Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York 10605, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York 10605, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cai
authors.affiliation: Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York 10605, USA.
authors.forename: Nana
authors.initials: N
authors.lastname: Fujiwara
authors.affiliation: 1] Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York 10605, USA [2] Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: Harriet
authors.initials: H
authors.lastname: Baker
authors.affiliation: 1] Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, New York 10605, USA [2] Brain and Mind Research Institute, Weill Cornell Medical College, New York, New York 10021, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Cave