Title: Epigenetics and schizophrenia: Integration of chromatin dynamics and animal behaviour
Funder: Wellcome Trust

Abstract: The aims of this project are to investigate the connections between environmental stress-induced changes in the euchromatic histone methyltransferase 1 gene (EHMT1), epigenetic regulation and behaviour. Our investigation will be divided into three stages which are designed to establish: 1) The effects of environmental stress on EHMT1 expression and methylation patterns; 2) The identification of EHMT1-mediated methylation patterns and target genomic loci; 3) Whether stress induced changes in EHMT1 expression and methylation lead to subsequent changes in target gene expression. Schizophrenia is a serious psychiatric disorder affecting approximately 1% of the population. Genetic factors are consistently found to account for a large percentage of the risks in developing the disease. Known environmental risks have also been identified. However, progress in understanding the aetiology and developmental trajectory of the disorder is seriously hampered both by the lack of consistency in findings and the entrenched state of the post mortem tissue often used for analysis. The contribution of both environmental and genetic risks suggests that there may be a significant epigenetic component to the elevated risks. A recent copy number variant screen of schizophrenia patients identified increased risks associated with either a deletion or duplication of histone methyltransferase gene EHMT19. EHMT1, also known as G9a-like protein (GLP), is a member of a complex set of site-specific lysine (K) methyltransferases (or KMTs) which transfer the methyl group S-adenosylmethionine (SAM) to lysine residues. GLP protein forms a multimeric complex with several protein families including G9a/EHMT2 in order to mediate monomethylation and dimethylation on lysine-9 of Histone 3 (H3K9me)11. EHMT1-mediate H3K9me2 marks chromatin sites for the transcriptional silencing of individual genes. Kirov et al. also reported several CNVs encoded members of the DLG family of Membrane Associated Guanylate Kinases (MAGUKs). Interestingly, EHMT1 has been found to directly regulate the DLG family members. In addition to finding a handful of highly penetrate CNVs, the case de novos were also found to be significantly enriched for the post-snynaptic density (PSD) proteome. This was further explained by specific enrichment in NMDAR and neuronal activity-regulated cytoskeleton-associated protein or ARC, both of which are postsynaptic signalling complexes9. Kirov et al.'s identification of related gene groups enriched in these CNVs provides a promising biological pathway for analysis. Furthermore their specific identification of NMDAR enrichment in these patients along with a recent report providing evidence that KMTs may directly mediated NMDA subunit expression in a highly specific manner bodes well with leading hypothesis on the role of NMDA hypofunciton in schizophrenia. Accumulating evidence reviewed below points to the direct role of EHMT1 in experience-dependent transcriptional regulation and cognition in both the developing and mature brain. In order to simplify, we will structure our investigation around the Kirov et al. report. We will focus on the DLG gene family and PSD-related gene expression and on NMDA receptor function.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: MENTAL HEALTH