Conserved Upstream Regulatory Regions in Mammalian Tyrosine Hydroxylase

• Published in: Molecular neurobiology 2018-09, Vol.55 (9), p.7340-7351
• Main Authors: Wang, Meng, Fones, Lilah, Cave, John W.
• Format: Article
• Language: English
• Subjects: Animals; Base Pairing - genetics; Base Sequence; Binding Sites; Biomedical and Life Sciences; Biomedicine; Biosynthesis; Catecholamines; CCCTC-Binding Factor - metabolism; Cell Biology; Chromatin; Conserved sequence; Conserved Sequence - genetics; Deoxyribonucleic acid; DNA; Forebrain; Gene regulation; Genome; Humans; Hydroxylase; Immunoprecipitation; Mammals; Mammals - genetics; Mice; Neurobiology; Neurology; Neurosciences; Nuclear receptors; Nucleotide sequence; Nurr1 protein; Olfactory bulb; Organ Specificity - genetics; Pax6 protein; Regulatory sequences; Regulatory Sequences, Nucleic Acid - genetics; Rodents; Sequence Alignment; Transcription factors; Transcription Factors - metabolism; Transcription, Genetic; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - genetics
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-018-0936-9

Tyrosine hydroxylase ( Th ) encodes the rate-limiting enzyme in catecholamine biosynthesis, and the regulation of its transcription is critical for the specification and maintenance of catecholaminergic neuron phenotypes. For many genes, regulatory genomic DNA sequences that are upstream of the proximal promoter control expression levels as well as region-specific expression patterns. The regulatory architecture of the genomic DNA upstream of the Th proximal promoter, however, is poorly understood. In this study, we examined the 11 kb upstream nucleotide sequence of Th from nine mammalian species and identified five highly conserved regions. Using cultured human cells and mouse olfactory bulb tissue, chromatin immunoprecipitation (ChIP) assays show that these conserved regions recruit transcription factors that are established regulators of Th transcription (such as NURR1, PITX3, FOXA2, MEIS2, and PAX6). This analysis also identified a conserved binding site for CTCF, and functional studies in cultured human cells and ChIP assays with mouse tissue show that CTCF is a novel regulator of Th transcription in the forebrain. Together, the findings in this study provide key insights into the upstream regulatory genomic architecture and regulatory mechanisms controlling mammalian Th gene transcription.