miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome

Abstract

Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT4 receptor gene HTR4 to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms HTR4b/i and putatively impairs HTR4 expression. Subsequent miRNA-profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. In vitro assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform HTR4b_2 lacking two of the three miRNA binding sites escapes miR-16/103/107 regulation in SNP carriers. We provide the first evidence that HTR4 expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or by diminished levels of miR-16 and miR-103 suggesting that HTR4 might be involved in the development of IBS-D.

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Item Type:	Article
Authors/Creators:	Wohlfarth, C Schmitteckert, S Härtle, JD Houghton, LA Dweep, H Fortea, M Assadi, G Braun, A Mederer, T Pöhner, S Becker, PP Fischer, C Granzow, M Mönnikes, H Mayer, EA Sayuk, G Boeckxstaens, G Wouters, MM Simrén, M Lindberg, G Ohlsson, B Schmidt, PT Dlugosz, A Agreus, L Andreasson, A D’Amato, M Burwinkel, B Bermejo, JL Röth, R Lasitschka, F Vicario, M Metzger, M Santos, J Rappold, GA Martinez, C Niesler, B
Copyright, Publisher and Additional Information:	© The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 4 October 2017 Published (online): 31 October 2017 Published: 31 October 2017
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Molecular Gastroenterology (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	03 Aug 2018 13:57
Last Modified:	08 Jul 2019 12:20
Status:	Published
Publisher:	Nature Publishing Group
Identification Number:	10.1038/s41598-017-13982-0
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:134115

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miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome

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