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  Polymorphism in Tmem132d regulates expression and anxiety-related behavior through binding of RNA polymerase II complex

Naik, R. R., Sotnikov, S. V., Diepold, R. P., Iurato, S., Markt, P. O., Bultmann, A., et al. (2018). Polymorphism in Tmem132d regulates expression and anxiety-related behavior through binding of RNA polymerase II complex. TRANSLATIONAL PSYCHIATRY, 8: 1. doi:10.1038/s41398-017-0025-2.

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Naik, Roshan R.1, 2, Autor           
Sotnikov, Sergey V.1, 2, Autor           
Diepold, Rebekka P.1, Autor           
Iurato, Stella3, Autor           
Markt, Patrick O.1, Autor           
Bultmann, Andrea1, Autor           
Brehm, Nadine1, Autor           
Mattheus, Tobias2, Autor
Lutz, Beat2, Autor
Erhardt, Angelika3, Autor           
Binder, Elisabeth B.3, Autor           
Schmidt, Ulrike1, Autor           
Holsboer, Florian4, Autor           
Landgraf, Rainer1, Autor           
Czibere, Ludwig1, 2, Autor           
Affiliations:
1Max Planck Institute of Psychiatry, Max Planck Society, ou_1607137              
2External Organizations, ou_persistent22              
3Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society, ou_2035295              
4Emeritiertes wissenschaftliches Mitglied, Max Planck Institute of Psychiatry, Max Planck Society, ou_2074301              

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Schlagwörter: ENVIRONMENTAL ENRICHMENT; GENE-EXPRESSION; PANIC DISORDER; GENOME BROWSER; MILD STRESS; NEURONS; TRANSCRIPTION; SCALE; MICE; ASSOCIATIONPsychiatry;
 Zusammenfassung: TMEM132D is a candidate gene, where risk genotypes have been associated with anxiety severity along with higher mRNA expression in the frontal cortex of panic disorder patients. Concurrently, in a high (HAB) and low (LAB) trait anxiety mouse model, Tmem132d was found to show increased expression in the anterior cingulate cortex (aCC) of HAB as compared to LAB mice. To understand the molecular underpinnings underlying the differential expression, we sequenced the gene and found two single-nucleotide polymorphisms (SNPs) in the promoter differing between both lines which could explain the observed mRNA expression profiles using gene reporter assays. In addition, there was no difference in basal DNA methylation in the CpG Island that encompasses the HAB vs. LAB Tmem132d promoter region. Furthermore, we found significantly higher binding of RNA polymerase II (POLR2A) to the proximal HAB-specific SNP (rs233264624) than the corresponding LAB locus in an oligonucleotide pull-down assay, suggesting increased transcription. Virus mediated overexpression of Tmem132d in the aCC of C57BL/6 J mice could confirm its role in mediating an anxiogenic phenotype. To model gene-environmental interactions, HAB mice exposed to enriched environment (HAB-EE) responded with decreased anxiety levels but, had enhanced Tmem132d mRNA expression as compared to standard-housed HAB (HAB-SH) mice. While LAB mice subjected to unpredictable chronic mild stress (LAB-UCMS) exhibited higher anxiety levels and had lower mRNA expression compared to standard-housed LAB (LAB-SH) mice. Chromatin immunoprecipitation revealed significantly higher binding of POLR2A to rs233264624 in HAB-EE, while LAB-UCMS had lower POLR2A binding at this locus, thus explaining the enhanced or attenuated expression of Tmem132d compared to their respective SH controls. To further investigate gene-environment interactions, DNA methylation was assessed using Illumina 450 K BeadChip in 74 panic disorder patients. Significant methylation differences were observed in two CpGs (cg26322591 and cg03283235) located in TMEM132D depending on the number of positive life events supporting the results of an influence of positive environmental cues on regulation of Tmem132d expression in mice.

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Sprache(n): eng - English
 Datum: 2018
 Publikationsstatus: Erschienen
 Seiten: 18
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: ISI: 000424024100001
DOI: 10.1038/s41398-017-0025-2
 Art des Abschluß: -

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Titel: TRANSLATIONAL PSYCHIATRY
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA : NATURE PUBLISHING GROUP
Seiten: - Band / Heft: 8 Artikelnummer: 1 Start- / Endseite: - Identifikator: ISSN: 2158-3188