Epigenetic profiling associated with environmental exposure stress for stratifying disease risk

Background

Air pollution and its toxic effects including inflammation, oxidative stress and DNA damage are detrimental to the lungs upon inhalation, as well as to more distant tissues of the cardiovascular system, brain, and reproduction via the systemic circulation. While the health hazards of many compounds in air pollution have yet to be untangled, atmospheric fine particulate matter (e.g. PM2.5) is estimated to cause 400,000 deaths a year across Europe from lung disease, cancer, and aggravation of chronic conditions such as cardiovascular disease and neurodegenerative disorders. 

It is important to know how environmental exposures during the life course can modify disease risk for individuals in the population, to stratify treatments and prevention to varying disease susceptibilities¹. Exposures can be associated with alterations in characteristic chemical modifications on genomic DNA, termed epigenetic marks. More knowledge of the epigenetic changes in DNA methylation resulting from environmental exposure is emerging but our understanding of the mechanisms is limited as to how these DNA methylation changes occur and how they may facilitate persistent cell trait changes associated with chronic diseases.

Aims

Epigenetic changes can be stably maintained in the absence of alterations to the genetic information in the genome. Epigenetic molecular mechanisms, involving modifications to the DNA and histone proteins, control gene expression patterns during normal development and have continuing roles in human health and disease. A research question is whether a record of environmental exposures can be identified within the epigenetic marks across the genome, the epigenome. We aim to derive epigenetic exposure profiles that can be used as biomarkers predictive of an individual’s disease risk. To increase mechanistic insight, we also aim to investigate possible links between such epigenetic changes, signalling pathways, and alterations in cell fate or function that may be increased in susceptible individuals. Integrative bioinformatics analysis of methylation changes with gene expression and other epigenome data in mouse models is likely to be more sensitive and identify mechanisms that are conserved and relevant in human². 

Training Outcomes

This study in collaboration with our consortium studying the mechanistic toxicology of pollutant exposures on mouse brain and other tissues and human cognitive function, offers multidisciplinary training opportunities in biomedical and clinical (toxicology, inflammation, cardiovascular, neuroscience and cognition sciences) and environmental aerosol science. It offers DTP training in Precision Medicine and expertise in epigenetics, stress signalling pathways, genomics and gene expression analyses (infinium methylation array, bisulfite seq, and RNA seq), and will build on wider bioinformatics research within the collaborative teams for training and support. 

References

1. Wattacheril JJ, Raj S, Knowles DA, Greally JM. Using epigenomics to understand cellular responses to environmental influences in diseases. PLoS Genet 2023 19(1): e1010567. https://doi.org/10.1371/journal.pgen.1010567

2. Arneson, A, Haghani, A, Thompson, MJ et al. A mammalian methylation array for profiling methylation levels at conserved sequences. Nat Commun 13, 783 (2022). https://doi.org/10.1038/s41467-022-28355-z

3. Schuller A, Montrose L. Influence of woodsmoke exposure on molecular mechanisms underlying Alzheimer's disease: existing literature and gaps in our understanding. Epigenet Insights. 2020 Sep 14;13:2516865720954873. doi: 10.1177/2516865720954873.

4. Li S, Nguyen TL, Wong EM, Dugué PA, Dite GS, Armstrong NJ, Craig JM, Mather KA, Sachdev PS, Saffery R, Sung J, Tan Q, Thalamuthu A, Milne RL, Giles GG, Southey MC, Hopper JL. Genetic and environmental causes of variation in epigenetic aging across the lifespan. Clin Epigenetics. 2020 Oct 22;12(1):158. doi: 10.1186/s13148-020-00950-1.