Accessible resource for integrated epigenomics studies (ARIES)

Lead Research Organisation: University of Bristol
Department Name: Faculty of Medicine and Dentistry

Abstract

Epigenetic studies are becoming a central focus of biological research internationally. Epigenetic profiles can serve as exposure markers and as prognostic or predictive biomarkers, with leukocyte methylation currently being the most commonly measured form of epigenetic modification, in the most readily obtainable tissue and one that has undergone epigenetic analysis in many investigations. In regard to this mode of analysis the Avon Longitudinal Study of Parents and their Children (ALSPAC) provides a unique potential resource, in having two-generational data and cord blood and later peripheral blood samples available, allowing for intrauterine influences, intergenerational transmission, change in methylation from birth through to pre-pubertal and post-pubertal age, and investigation of how methylation patterns predict and change with development. Such methylation data would be linked to the extensive exposure, genotype and phenotype data available in ALSPAC. The human data will be coupled with rodent data documenting the relationship between leukocyte and other tissue methylation and gene expression and rodent model tissue banks related to over-nutrition, obesity and ageing. Additional rodent tissues will be banked for future analysis upon request. Data generated will be uploaded for browsing on a custom web-based interface developed specifically for this initiative which will permit the integration of data from multiple sources from both human and rodent sources. The user will have access to data exploration utilities, a graphical genome browser and interactive graphical views of data relationships. The integration of data on epigenetic profiles in this intensively characterised human cohort with rodent epigenetic and transcriptomic data to generate an accessible resource to enhance research in the field of epigenetics for the benefit of the wider scientific community represents a considerable bioinformatic undertaking. We will draw on the expertise of leading scientists in the field of epigenetics and population-based human cohort studies to generate relevant data and combine this with up to date and highly skilled bioinformatics input (developed with substantive previous investment from the BBSRC) to meet our stated objectives. In combination, the proposed generation of biological data together with state of the art bioinformatic tools for data integration and access, would provide an unequivocally world-leading resource for epigenetic studies.

Technical Summary

Serial samples taken at multiple time points across the lifecourse from 1,000 mother-child pairs from ALSPAC will be used to generate genome-wide DNA methylation. The Illumina 450K human methylation array will be used to analyse samples from birth, age 7 and age 15-17 in 1,000 children and samples taken during pregnancy and 17 years later from their mothers. These data will be complemented by methylome sequencing of both the 5-methylcytosine and 5-hyroxymethylcytosine fractions of the genome which will be isolated by immuno-precipitation and sequenced using a next-generation platform. Tandem genome wide methylation and gene expression analysis will be undertaken in mouse tissues (leukocytes, adipose, muscle, liver) using a custom NimbleGen methylation array and Affymetrix gene ST arrays respectively. Further mouse tissues will be harvested and banked for future investigation upon request. The complex primary data generated will be processed and fully integrated using the Ondex system that has been developed under the SABR initiative. In addition to the facility to view these data in an open access browser, users will have the opportunity to access extensive exposure and phenotype information from the ALSPAC cohort using the existing infrastructure. The project will run for 2 years and be managed by a team of academics who have a proven track record in large scale collaborative research and the provision of data and information to the wider scientific community. An international Scientific Advisory Board of leading scientists in epigenetics and bioinformatics will contribute to the oversight of ARIES.

Planned Impact

The ARIES project draws together complementary skills in laboratory, population and bioinformatic aspects of epigenetics to create a unique resource that will be of considerable value to a broad bioscience community spanning both academia and industry, both in the UK and internationally. The population of researchers engaged in the field of epigenetics is growing exponentially and the need for large scale genome-wide locus specific epigenomic data in combination with phenotypic and exposure data has been identified as a research priority by several recent high impact publications. Such information would provide understanding of how the epigenome differs between individuals, how it changes through the life course during the natural ageing process, identify factors that mediate these changes and provide insight into their physiological consequences. The ARIES project will address this knowledge and resource deficit by capitalising on recent advances in genome wide epigenetic methodologies and the availability of samples from a unique parent and child cohort (ALSPAC) which has been extensively phenotypically and genetically characterised over the past 20 years. The inclusion of data from mice to address tissue-specificity of the epigenotype, another major focus of current debate in the field, provides an extra and important dimension. The project will utilise advanced bioinformatic tools to establish a facility to amass, integrate and disseminate multi-dimensional biological information. The incorporation of computational tools and web-based technology is increasingly a feature of scientific research and this project will exemplify the societal impact that such advances can have. As reflected by the letters of support from both academia and industry in the UK, Europe and further afield, the ARIES resource will be utilised widely and accelerate scientific advances in this rapidly emerging field. The proposed timescale of 2 years places ARIES in a highly competitive position, with tangible output well in advance of much larger, more technically demanding global initiatives currently being discussed. Epigenetics has captured the headlines in both the popular and scientific press in recent years partly due to the promise it holds in providing a route through which gene expression can be modulated by pharmacological, dietary, lifestyle or perhaps behavioural interventions. This is particularly important in modern society where in countries such as the UK, the population is ageing and governments are faced with ensuring that the 'health span' of the population increases in parallel with the 'lifespan'. Furthermore, epigenetic mechanisms are clearly important in optimal development, and possible cognitive (and other) deficits of considerable importance in economic and human capital terms may arise through such processes. Any interventions that optimise development and ageing could therefore have a major societal impact. Research in this field is actively being pursued in many domains from basic science laboratories to the pharmaceutical industry. Industrial colleagues have therefore justifiably highlighted the potential that ARIES represents in enhancing the efforts in preventive medicine, the discovery of novel therapeutic targets and the possible application of epigenetic factors as biomarkers of efficacy of interventions and treatments. Modification of the epigenotype is a considerably more tractable target for intervention and prevention strategies than modification of the genotype and therefore has the potential to make a greater impact on public health policies and the wellbeing of the population. Advances in any of these areas would bring considerable economic gain and maintain the UK at the forefront of advances in this area.

Publications

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Morris JA (2017) Epigenome-wide Association of DNA Methylation in Whole Blood With Bone Mineral Density. in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

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Lewis SJ (2013) Approaches for strengthening causal inference regarding prenatal risk factors for childhood behavioural and psychiatric disorders. in Journal of child psychology and psychiatry, and allied disciplines

 
Description This research has generated a large scale resource for epigenetic epidemiology research.. It is the first resource of its kind to make large scale DNA methylation data from a population based cohort, generated from serial samples from the same individuals, openly accessible for research use. It has resulted in numerous published outputs involving both methodological developments and epidenome-wide association study findings. ARIES is a major (founding) contributor to several epigenomic consortia.
Exploitation Route Data are available via ALSPAC and are widely used by researchers from numerous international institutions.
Sectors Environment,Healthcare