Grant: Team Grant: Epigenomics of Complex Diseases

The recent surge in asthma (A) and Type 1 diabetes (T1D) incidence is often attributed to changes in environmental exposures, notably early infections. GWAS has revealed tens of loci where associated variants lie in non-coding, regulatory DNA regions active in CD4+ T-cells. The importance of subsets of T-helper cells and their opposite polarization in T1D and A prompts the examination of interactions of genetic and environmental risk factors in the epigenomes of T-cells. We have built a translational research plan using our deep clinical, immunological, and genomic expertise and resources. Using comprehensive epigenome-wide association studies (EWAS) in large, well-phenotyped French cohorts with longitudinal sampling and familial or carefully matched controls, we will pinpoint methylation variants associated with A and T1D. Using IHEC datasets and longitudinal sampling of patients' T-cell fractions, we will further characterize these regions by deeper epigenome mapping to assess their impact on immune cell function. High value targets that impact T1D/A risk and progression will be validated by epigenome editing in vitro and investigated in vivo using existing animal models. Joint development of tools, resources and analytical approaches enable maximum power of T1D and A epigenome dissection. The validation and follow-up of epigenome associations will reveal molecular mechanisms and function of epigenome perturbation. To achieve these milestones we develop tools for studying population chromatin, small cell epigenomics and novel statistical/bioinformatics approaches to advance EWAS. This will provide first fully characterized epigenomic profiling underlying A/T1D risk/progression, amenable to development of new therapeutics and prevention strategies, and a general paradigm for EWAS in complex diseases.