Endogenous viral elements in type 1 diabetes pathogenesis

Type 1 diabetes (T1D) is one of the most common chronic diseases of the endocrine system, associated with several life-threatening co-morbidities. While the etiopathogenesis of T1D remains elusive, a combination of genetic susceptibility and environmental factors, such as microbial infections, are believed to be involved in the development of the disease. Prime model for studying the genetic component of T1D predisposition encompasses polymorphisms within the HLA region, responsible for the specificity of antigen presentation to lymphocytes. Apart from polymorphisms, genomic reorganisation, caused by repeat elements and endogenous viral elements (EVEs), might be involved in T1D predisposition. Such elements are human endogenous retroviruses (HERV) and non-LTR retrotransposons including long and short interspersed nuclear elements (LINEs and SINEs). In line with their parasitic origins and selfish behaviour, EVE-imposed gene regulation is a major source of genetic variation and instability in the human genome and may provide the missing link between genetic susceptibility and environmental factors long thought to contribute to T1D onset. The purpose of the project is to elucidate the involvement of EVEs in T1D predisposition. We hypothesise that EVEs alter specific genomic regions associated with the immune system, favouring clonal propagation of the cells with altered genomic regions and thus influencing the development of type 1 diabetes. Children with newly diagnosed T1D administered at the Department of Paediatric Endocrinology, Diabetes, and Metabolic Diseases at the UMC Ljubljana over one year will participate in our study. Approx. 50 newly diagnosed participants will be screened for active EVEs to identify those with the significantly expressed EVEs for further single cell-specific transcriptomics. Identification of auto-reactive immune cell subtypes with differentially expressed EVEs will be the foundation for fluorescence-activated cell sorting. EVE expression will be confirmed and high-quality personalised assembled genomes will be constructed from sorted immune cell subtypes. These will serve as a reference and will enable precise prediction of EVE integration/restriction sites to overcome the genetic complexity of investigated HLA and other regions. Finally, predicted sites will be confirmed on an independent cohort of newly diagnosed children with T1D to ascertain their potential for biomarkers and therapeutic targets. Each stage of the proposed project will add relevant scientific value to the existing field while representing a foundation for informed decisions in the next stage. In case of bottlenecks, contingency strategies are provided in order to accomplish planned objectives and produce high-impact results with great potential for early diagnosis and therapy with the final goal of reverting or even preventing the development and progression of diabetes.