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Multiple coregulatory control of tyrosine hydroxylase gene transcription.

ABSTRACT: Despite ubiquitous expression and a high level of metastasis-associated protein 1 (MTA1) coregulator, the physiological role of the MTA1 coactivator remains unknown. We found that MTA1 is a bona fide coactivator and stimulator of tyrosine hydroxylase (TH) transcription in neuronal cells and that MTA1-null mice had lower TH expression in the striatum and substantial nigra. MTA1 physically achieves these functions by interacting directly with DJ1 (Parkinson disease 7) and in turn recruits the DJ1/MTA1/RNA polymerase II complex to the bicoid binding element (BBE) in the TH promoter. Furthermore, we found that the MTA1/DJ1 complex is required for optimum stimulation of the TH expression by paired like homeodomain transcription factor (Pitx3) homeodomain transcription factor and that the MTA1/DJ1 complex is recruited to the TH gene chromatin via the direct interaction of MTA1 with Pitx3. These findings reveal a role for MTA1 as an upstream coactivator of TH and advance the notion of polygenic regulation of a disease-causing gene by coordinated interactions of three regulatory proteins.

SUBMITTER: Reddy SD

PROVIDER: S-EPMC3054001 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Multiple coregulatory control of tyrosine hydroxylase gene transcription.

Reddy Sirigiri Divijendra Natha SD Rayala Suresh K SK Ohshiro Kazufumi K Pakala Suresh B SB Kobori Nobuhide N Dash Pramod P Yun Sung S Qin Jun J O'Malley Bert W BW Kumar Rakesh R

Proceedings of the National Academy of Sciences of the United States of America 20110222 10

Despite ubiquitous expression and a high level of metastasis-associated protein 1 (MTA1) coregulator, the physiological role of the MTA1 coactivator remains unknown. We found that MTA1 is a bona fide coactivator and stimulator of tyrosine hydroxylase (TH) transcription in neuronal cells and that MTA1-null mice had lower TH expression in the striatum and substantial nigra. MTA1 physically achieves these functions by interacting directly with DJ1 (Parkinson disease 7) and in turn recruits the DJ1/ ...[more]

PMID: 21368136

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Project description:The mesotelencephalic dopamine system shows substantial genetic variation which fundamentally affects normal and pathological behaviors related to motor function, motivation, and learning. Our earlier radioenzyme assay studies demonstrated significantly higher activity of tyrosine hydroxylase (TH), the first and rate limiting enzyme in the biosynthesis of catecholamine neurotransmitters, in the substantia nigra-ventral tegmental area of BALB/cJ mice in comparison with that of C57BL/6ByJ mice. Here, using quantitative immunoblotting and immunocytochemistry, we tested the hypothesis that mesencephalic TH protein content and number of nigral TH-positive neurons show strain-dependent differences in C57BL/6ByJ and BALB/cJ parallel to those observed in the TH activity studies. Immunoblotting experiments detected significantly higher mesencephalic TH protein content in BALB/cJ in comparison to C57BL/6ByJ (P<0.05). Immunocytochemical studies demonstrated that the number of TH-positive cells in substantia nigra was 31.3% higher in BALB/cJ than that in C57BL/6ByJ (P<0.01), while the average dopamine neuron volume was not significantly different. In a search for candidate genes that modulate TH content and the size of mesencephalic dopamine neuron populations we also studied near-isogenic mouse sublines derived from the C57BL/6ByJ and BALB/cJ progenitor strains. A whole-genome scan with 768 single nucleotide polymorphism markers indicated that two sublines, C4A6/N and C4A6/B, were genetically very similar (98.3%). We found significantly higher mesencephalic TH protein content in C4A6/B in comparison to C4A6/N (P=0.01), and a tendency for higher number of dopamine neurons in the substantia nigra in C4A6/B in comparison to C4A6/N, which, however, did not reach statistical significance. To identify the genetic source of the TH content difference we analyzed the single nucleotide polymorphism (SNP) genotype data of the whole-genome scan, and detected two small differential chromosome segments on chr. 13 and chr. 14. Microarray gene expression studies and bioinformatic analysis of the two differential regions implicated two cis-regulated genes (Spock1 and Cxcl14, chr. 13), and two growth factor genes [bone morphogenetic protein 6 (Bmp6) (chr. 13), and fibroblast growth factor 14 (Fgf14) (chr. 14)]. Taken together, the results suggest that (1) nigral dopamine neuron number and TH protein content may be genetically associated but further studies are needed to establish unequivocally this linkage, and (2) Spock1, Cxcl14, Bmp6, and Fgf14 are novel candidates for modulating the expression and maintenance of TH content in mesencephalic dopamine neurons in vivo.

Dataset Information

Multiple coregulatory control of tyrosine hydroxylase gene transcription.

Publications

Multiple coregulatory control of tyrosine hydroxylase gene transcription.

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