Date of Award

2014

Document type

Thesis

Degree Name

MSc by research (Master of Science by research)

First Supervisor

Professor David Cotter

Second Supervisor

Dr Melanie Foecking

Third Supervisor

Dr Gerard Cagney

Keywords

Schizophrenia - genetics, Epigenomics

Abstract

Genetic factors have been widely implicated in the study of schizophrenia. Twin and adoption studies estimate the heritability at approximately 80%. The rate of discordance between monozygotic twins is estimated at 65%, indicating that other factors influence the risk of developing schizophrenia. Many environmental factors have been identified that affect one's likelihood of developing this disorder. Examples of these factors include exposure to drugs, psychological stress and nutritional deficiencies, especially during critical time periods, such as prenatal and adolescence periods [1, 2].

This implies that the interplay between genetic and environmental factors is important in the development of schizophrenia but the mechanism by which external influences affect one's gene expression is poorly understood. Epigenetics provides one mechanism by which these factors may interact to contribute to disease. Epigenetic information is inherited via alterations to DNA methylation patterns, histone posttranslational modifications (hPTMs) and microRNA expression aberration [1-3]. These are thought to modify gene and subsequent protein expression and contribute to disease risk. Critically, these alterations can occur without a change in the underlying genetic code and are thus termed 'epigenetic'. Epigenetic modifications can be induced by environmental factors [1-3].

The aim of this project was to optimise a technique to identify hPTMs in brain regions implicated in schizophrenia using mass spectrometry. As part of this project, the technique was applied to the hippocampus of a prenatal stress mouse model that been shown to mimic certain features of schizophrenia. The intention of the technique is to assess the influence of environment on gene expression levels via hPTMs in this mouse model.

Overall, twenty-six hPTMs were observed in prenatally stressed and control groups. The hPTMs were searched against relevant databases to evaluate previously associated gene expression states and diseases. Future studies will attempt to quantify hPTM expression intensities to compare differential expression levels between model and control samples. Through the identification of new and differentially expressed hPTMs in prenatally stressed and control samples, this technique has the potential to provide important insights into the epigenetic mechanism of schizophrenia.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.

File Size

6.11 MB

Comments

A thesis submitted for the degree of Master of Science from the Royal College of Surgeons in Ireland in 2014.

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