Abstract
As regulators of gene expression, microRNAs (miRNAs) are likely to play an important role in the development of disease. In this study we present a large-scale strategy to identify miRNAs with a role in the regulation of neuronal processes. Thereby we found variant rs7861254 located near the MIR204 gene to be significantly associated with schizophrenia. This variant resulted in reduced expression of miR-204 in neuronal-like SH-SY5Y cells. Analysis of the consequences of the altered miR-204 expression on the transcriptome of these cells uncovered a new mode of action for miR-204, being the regulation of noncoding RNAs (ncRNAs), including several miRNAs, such as MIR296. Furthermore, pathway analysis showed downstream effects of miR-204 on neurotransmitter and ion channel related gene sets, potentially mediated by miRNAs regulated through miR-204.
Highlights
MiRNAs are short regulatory noncoding RNA molecules
To study the function of miRNA genes in neurological diseases and to investigate which miRNA genes regulate neuronal processes, we created a Multiplex Amplification of Specific Targets for Resequencing (MASTR) assay [17,18] for the amplification of 289 brain expressed miRNA genes. This assay was subsequently used in combination with massively parallel sequencing for variant discovery within the selected miRNA genes in patients with schizophrenia or idiopathic generalized epilepsy (IGE) and in Swedish and Belgian and Dutch control individuals
A total of 265 variants were identified in the schizophrenia patients and the Swedish control group and 315 variants were identified in the IGE patients and the Belgian/Dutch control group (Tables A and B in S1 File)
Summary
MiRNAs are short regulatory noncoding RNA molecules. Their maturation process consists of two consecutive cleavage steps. The first step takes place in the nucleus, whereby the Microprocessor complex, consisting of ribonuclease Drosha and its cofactor DGCR8, frees the hairpin structured precursor miRNA (pre-miRNA) from the primary miRNA transcript (pri-miRNA) [1,2]. Posttranscriptional regulation of messenger RNAs (mRNA) in the cytosol by miRNAs is well studied [8]. To this canonical cytoplasmic role of miRNAs, mature miRNA-Argonaute complexes can be shuttled back into the nucleus by Importin-8 [9]. Many mature miRNAs have been shown to be present in the PLOS ONE | DOI:10.1371/journal.pone.0144428 December 29, 2015
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
