Dataset Information

A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety.

ABSTRACT: Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAF_cases?=?0.431, MAF_controls?=?0.368) upstream of MIR579 was associated with panic disorder in patients (p_allelic?=?0.004, n_cases?=?506, n_controls?=?506) and with higher trait anxiety in healthy individuals (p_ASI?=?0.029, p_ACQ?=?0.047, n?=?3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p?=?0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270)?=?5.47, p?=?0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.

SUBMITTER: Hommers LG

PROVIDER: S-EPMC6195525 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety.

Hommers L G LG Richter J J Yang Y Y Raab A A Baumann C C Lang K K Schiele M A MA Weber H H Wittmann A A Wolf C C Alpers G W GW Arolt V V Domschke K K Fehm L L Fydrich T T Gerlach A A Gloster A T AT Hamm A O AO Helbig-Lang S S Kircher T T Lang T T Pané-Farré C A CA Pauli P P Pfleiderer B B Reif A A Romanos M M Straube B B Ströhle A A Wittchen H-U HU Frantz S S Ertl G G Lohse M J MJ Lueken U U Deckert J J

Translational psychiatry 20181019 1

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating ...[more]

PMID: 30341278

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Project description:The aim of the present study was to identify the differentially expressed microRNAs (DEMs) between Lynch syndrome (LS) and the normal colonic (N-C) control samples, predict the target genes (TGs) and analyze the potential functions of the DEMs and TGs. The miRNA expression dataset GSE30454, which included data of 13 LS and 20 N-C tissue samples, was downloaded from the Gene Expression Omnibus. The classical t-test in Linear Models for Microarray Data package was used for DEM identification. TG prediction was performed using 5 databases. The regulatory network of the DEMs and their TGs was constructed using Cytoscape. Functional and pathway enrichment analysis was performed. The transcription factors (TFs), tumor-associated genes (TAG) and tumor suppressor genes (TSGs) were then identified. Three key DEMs hsa-miR-137, hsa-miR-520e, and hsa-miR-590-3p were identified. Hsa-miR-520e and hsa-miR-137 had 4 common TGs, including SNF related kinase, metal-regulatory transcription factor 1 (MTF1), round spermatid basic protein 1 and YTH N6-methyladenosine RNA binding protein 3; hsa-miR-590-3p and hsa-miR-137 had 14 common TGs, including NCK adaptor protein 1 (NCK1), EPH receptor A7, and stress-associated endoplasmic reticulum protein 1; hsa-miR-590-3p and hsa-miR-520e had 12 common TGs, including Krüppel-like factor (KLF) 13, twinfilin actin binding protein 1, and nuclear factor I B. Through the functional and pathway enrichments analysis, MTF1 was involved in regulation of gene expression and metabolic processes, and sequence-specific DNA binding TF activity. KLF13 was involved in regulation of gene expression and regulation of cellular metabolic processes. NCK1 was enriched in the axon guidance pathway. In addition, the functional and pathway enrichment analysis showed certain TGs, such as hypoxia-inducible factor 1α, AKT serine/threonine kinase 2, and rapamycin-insensitive companion of mammalian target of rapamycin, participated in the mTOR signaling pathway. The 3 key DEMs hsa-miR-137, hsa-miR-520e, and hsa-miR-590-3p may have important roles in the process of LS.

Dataset Information

A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety.

Publications

A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety.

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