title: Expression of tyrosine hydroxylase is epigenetically regulated in neural stem cells.
abstract: Tyrosine hydroxylase (TH) is the first and rate-limiting enzyme in the biosynthesis of catecholamines, and its expression is regulated in a developmental stage- and cell type-specific manner. Our previous work suggested that the genetic elements responsible for cell type-specific expression of TH were in the repressor region of the TH promoter between -2187 and -1232 bp. To investigate the molecular mechanisms underlying the specificity of TH expression, the DNA methylation patterns of the CpG islands in the repressor region of the TH promoter were examined in human neural stem cells (NSCs) and dopaminergic neuron-like cells. Using a bisulfite sequencing method, we found that the cytosine residues of CpG islands within the NRSE-R site were specifically methylated in NSCs, but not in SH-SY5Y neuroblastoma cells. In NSCs, CpG methylation correlated with reduced TH gene expression, and inhibition of DNA methylation with 5-azacytidine restored TH expression. Furthermore, methyl-CpG binding domain proteins (MBDs) bound to the highly methylated X-1 and X-2 regions of the TH gene in NSCs. Taken together, these results suggest that region-specific methylation and MBDs play important roles in TH gene regulation in NSCs.
authors: Institute for Medical Science, Ajou University School of Medicine, Suwon, Republic of Korea.
authors: Jae Won
authors: JW
authors: Yang
authors: Eun Yang
authors: EY
authors: Choi
authors: Mi Jung
authors: MJ
authors: Park
authors: Myung Ae
authors: MA
authors: Lee
mesh_terms: D001374:Azacitidine / Q000494:pharmacology; D001483:Base Sequence; D018899:CpG Islands / Q000187:drug effects; D003596:Cytosine / Q000737:chemistry; D019175:DNA Methylation / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000201:enzymology*; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008969:Molecular Sequence Data; D058953:Neural Stem Cells / Q000201:enzymology*; D011401:Promoter Regions, Genetic; D017422:Sequence Analysis, DNA; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*
chemical_list: D003596:Cytosine; D014446:Tyrosine 3-Monooxygenase; D001374:Azacitidine