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Research

Psychiatric Epigenetics

The SGDP Psychiatric Epigenetics Group was established in 2007 and utilises the cutting-edge facilities at the SGDP to explore the role of epigenetic processes in behaviour and susceptibility to neuropsychiatric disease, including elucidating how external environmental factors may bring about long-term changes in gene expression via epigenetic alterations, for example. Our research is split across two institutions, with labs based at the University of Exeter Medical School and the Institute of Psychiatry, Psychology and Neuroscience, King's College London.

Sequencing the genome was only the first step in our quest to understand how genes are expressed and regulated. Sitting above the DNA sequence is a second layer of information (the ‘epigenome’) that regulates several genomic functions, including when and where genes are turned-on or -off. ‘Epigenetics’ refers to the reversible regulation of gene expression mediated principally through changes in DNA methylation and chromatin structure. Epigenetic processes are essential for normal cellular development and differentiation, and allow the regulation of gene function through non-mutagenic mechanisms. Unlike the DNA sequence, which is stable and strongly conserved, epigenetic processes are tissue-specific, developmentally-regulated and relatively dynamic. For example, mounting evidence suggests that epigenetic processes can be influenced by exposure to a range of external environmental factors, either globally or at specific loci.

Epigenetic dysfunction can explain numerous epidemiological, clinical, and molecular peculiarities associated with psychiatric disorders that are difficult to rectify using traditional gene- and environment-based approaches. These include the incomplete concordance between MZ twins; a fluctuating disease course with periods of remission and relapse; sexual dimorphism; peaks of susceptibility to disease coinciding with major hormonal rearrangements, and parent-of-origin effects. Our lab aims to explore the role of epigenetic factors in mediating susceptibility to a number of psychiatric conditions including schizophrenia, bipolar disorder, major depression, attention-deficit hyperactivity disorder, and autism.

Below are some of the studies that our research groups are currently working on as well as some of the methods that we currently employ and are also developing.

Epigenetic Profiling in Discordant MZ Twins

 

 Across most psychiatric disorders, monozygotic (MZ) twin concordance is far from 100% suggesting that non-genetic factors are likely to be involved in disease aetiology. We are investigating the role of epigenetic variation in mediating phenotypic variation between genetically-identical individuals. We do this by using cutting-edge methylomic profiling methods to assess disease-associated epimutations in MZ twins discordant for a range of neuropsychiatric disorders including ADHD, autism, bipolar disorder and schizophrenia.

We are also interested in comparing the epigenetic profile of MZ and  dizygotic (DZ) twins to estimate the contribution of heritable and environmental factors to the epigenome.

To view one of our recent articles which used a longitudinal twin study to investigate X-chromosome inactivation, click here.

Allele-specific DNA Methylation

A major research focus of our group is to examine patterns of allele-specific DNA methylation (ASM) across the genome, to identify novel imprinted regions of the genome and their role in mediating parent-of-origin effects in psychiatric disorders. We are interested in uncovering both cis-mediated ASM (i.e. looking for genetic influences on local epigenetic signatures) and novel regions of the genome characterised by parental-origin-dependent DNA methylation (i.e. genomic imprinting).

Click here for one of our articles on widespread genome-wide allelic skewing DNA methylation and here for a further article we published on the implications of this.

Paternal Age

We are looking at uncovering the mechanism behind the association between advanced paternal age and risk for neuropsychiatric disorders. Increasing paternal age has been epidemiologically associated with several psychiatric disorders including autism, bipolar disorder and schizophrenia. The mechanism behind this association is unknown, but is likely to involve de novo genomic alterations and/or epigenetic variation.

We recently published results from a rodent model of increased paternal age, reporting deficits in social and exploratory behaviour in the offspring of older male mice, which can be found here. We are also now currently performing molecular studies on tissue obtained from these animals to look for evidence for de novo genomic/epigenomic changes associated with paternal age.

Methods and Approaches

We use a range of cutting-edge epigenomic methodologies to investigate DNA methylation. Genomewide DNA methylation profiling is performed using high-resolution microarrays (NimbleGen, Illumina and Affymetrix) or next-generation sequencing following enrichment of i) the unmethylated genomic fraction (via cleavage with methylation-sensitive restriction enzymes and amplification) and ii) the methylated genomic fraction (via methylated DNA immunoprecipitation).

We are currently optimising the use of next-generation sequencing to obtain enhanced coverage of genomewide DNA methylation patterns. Quantitative gene-specific DNA methylation profiling across specific genomic regions is performed using the Sequenom EpiTYPER system and Pyrosequencing on bisulphite-treated DNA. We are currently optimising our protocols for high-throughput analyses utilising the robotics facilities at the MRC SGDP Centre.

As part of the SGDP's Epigenetics Resource, we have developed a panel of optimised and verified assays (Psychiatric EipPanel) for profiling DNA methylation across key brain-expressed loci and candidate genes implicated in the aetiology of psychiatric illness and behaviour. Assays have been designed for human, mouse and rat and are based on both the Sequenom EpiTYPER platform and Pyrosequencing.

 

 

Team

Jonathan Mill: Professor in Psychiatric Epigenetics

Chloe Wong: Lecturer in Epigenetics

Rebecca Smith: Postdoctoral Research Fellow

Sarah Marzi: PhD student

Helen Spiers: PhD student

 

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