Regulation at the schizophrenia-associated MIR137 locus and repetitive DNA in the regulation and evolution of brain-related pathway

• Main Author: Gianfrancesco, O.
• Other Authors: Quinn, John ; Bubb, V. J. ; Collier, David
• Published: University of Liverpool 2018
• Subjects: 615.1
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.755631

Maintaining the appropriate transcriptional balance in the cell is a complex process involving numerous mechanisms, including the action of transcription factors and non-coding regulatory elements. Such processes are key to maintaining healthy central nervous system (CNS) functioning, and can be modulated through the interaction of both genes and environment in a ‘G x E’ mechanism. If the regulation of a certain gene or gene set is altered inappropriately in the brain, this can result in neuronal dysfunction which may contribute to psychiatric or CNS conditions. This thesis primarily aimed to extend our understanding of transcriptional regulation at the MIR137 schizophrenia-associated locus, and to add to our understanding of the role of repetitive DNA and retrotransposons in the regulation and evolution of genes involved in wider CNS pathways. The chromosome 1p21.3 locus encompassing the microRNA, MIR137, has been repeatedly highlighted by GWAS as one of the most robust loci for association with schizophrenia. The evidence presented in this thesis identified multiple evolutionary conserved regions (ECRs) which act as transcriptional regulators at this locus, as well as a regulatory gene network comprising MIR137 and the transcriptional regulators REST and EZH2, which are likely to modulate the expression of multiple CNS- and schizophrenia-associated gene sets. Extending our view of the MIR137 locus identified a brain-expressed RNA, EU358092, which shared near identical expression and regulatory profiles to MIR137, suggesting potential co-expression and -regulation of RNAs across this locus. The second half of this thesis explored repetitive DNA, including variable number tandem repeats (VNTRs) and the retrotransposon subfamilies, Long Interspersed Nuclear Elements (LINEs) and SINE-VNTR-Alus (SVAs), which have been shown to act as modulators of gene expression. Common polymorphisms in the VNTR containing MIR941, a human-specific, brain expressed microRNA at chromosome 20q13.3, resulted in altered copy number of MIR941, with two genotypes being specific to a schizophrenia cohort. SVAs were implicated in the recent evolution of multiple zinc finger loci, which may have had the potential to alter the regulation of large transcriptional networks in a species-specific manner, while LINE elements were likely to have been involved in recent genomic remodelling around GABA and glutamate signalling genes. Taken together, the work contained in this thesis considered the roles of a wide range of DNA elements with relevance to CNS-expressed genes, from the oldest and most highly conserved regions of the genome, to the most recent retrotransposon insertions. This work identified roles for these elements in the evolution and regulation of genes involved in schizophrenia risk and neuroprotection, and further identified gene networks and additional transcripts which may contribute to the maintenance of healthy brain functioning. The impact of genetic variation at these regions - in the form of single nucleotide polymorphisms (SNPs), altered VNTR copy number, or polymorphic retrotransposon insertions - and their effect on CNS functioning, has been a key theme throughout this work. In conclusion, this would provide evidence to suggest that genetic polymorphisms which alter the function, size, or location of such elements at loci involved in brain-related processes could contribute to schizophrenia risk in a way that would likely be modulated through an interaction between environmental stimuli and genotype.