Studying microRNA function from a genetic perspective

Date: 22 September 2015

Venue: UAntwerp, Campus Drie Eiken, Building Q - Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (Antwerp)

Time: 4:00 PM - 6:00 PM

Organization / co-organization: Sophia Cammaerts

PhD candidate: Sophia Cammaerts

Principal investigator: Jurgen Del-Favero

Short description: PhD defence Sophia Cammaerts - Faculty of Pharmaceutical, Biomedical and Veterinary Sciences - Department of Biomedical Sciences



Abstract

MicroRNAs (miRNAs) are small RNA molecules regulating gene expression in the cell. Individual miRNAs target a large number of mRNAs and mRNAs may be regulated by several miRNAs, resulting in a complex layer of expression regulation. However, our understanding of the function of specific miRNAs is still very limited.

As miRNAs exert their function at the RNA level, most research exploring the functionality of individual miRNAs also starts at this level. While this has led to many insights in miRNA regulation, for many tissues, such as brain, this approach is not easily applicable or not applicable at all. In this PhD project, we therefore researched an alternative and complementary approach for the identification of miRNAs involved in the regulation of neuronal pathways, starting at the genomic level. In our approach, a large-scale genetic variant screening of brain expressed miRNA genes is performed in individuals with a neurological disease and is compared to controls. Thereby we employ the genetic association of miRNA variants with the neurological phenotype as an indication for a miRNA to have a potential role in the regulation of neuronal processes. Because we aim to identify variants that can be used to study the wild type function of the miRNA gene in question, we also assess the predicted impact of the variant on the miRNA. Taking into account the association and prediction results, we prioritize the most interesting variants for functional follow-up.

To enable this strategy, we developed software for the in silico prediction of the functional effect of large sets of miRNA variants and an assay allowing the simultaneous amplification of 289 brain expressed miRNA genes. We then applied the strategy to three neurological diseases: schizophrenia, bipolar disorder and idiopathic generalized epilepsy. Identification of variants in genes MIR137 and MIR204 and functional follow-up showed that they affect synaptogenesis, neurotransmission and ion channel pathways. These results validated the usefulness of our strategy to identify miRNAs regulating neuronal pathways and further strengthened the role of miRNAs in the etiology of these diseases. Moreover, the tools that were developed during this project can be utilized in many applications.