Involvement of epigenetic mechanisms in disease inheritance and pathogenesis of Multiple Sclerosis (MS) with a focus on genomic imprinting and DNA methylation in CD4+ T cells

摘要

Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative disease driven byautoreactive CD4+ T cells. Disease etiology is mediated by a strong interplay between geneticand environmental factors implying a role for epigenetic mechanisms. Epigenetics is definedas the study of mechanisms, such as DNA methylation, histone modifications and non-codingRNAs, that result in changes of gene expression without altering the underlying genetic code.Genomic imprinting, one of the most-studied epigenetic marking processes, causes a gene tobe expressed only from the maternally or paternally inherited chromosome.In this thesis we investigate the contribution of epigenetic mechanisms to the etiology andpathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis(EAE).We investigated the impact of parent-of-origin, in particular genomic imprinting, using twolarge populations of reciprocal backcross rats and identified that epigenetic mechanisms playa role in EAE inheritance and pathogenesis. Using a transgenic mouse model, we discoveredthat the imprinted Dlk1 gene impacts the underlying immune responses in EAE. Furtherdiscovery of imprinted genes, using RNA sequencing in adult reciprocal hybrid rats, providedadditional insights into the underlying mechanisms of how imprinted genes could interferewith the immune response in EAE by modulating CD4+ T cell function.Utilizing a genome-wide approach to identify DNA methylation changes between MSpatients and controls in CD4+ T cells and monocytes revealed how DNA methylation as anepigenetic mark can impact the function of CD4+ T cells in MS. We identified that DNAmethylation acts as a mediator of the major MS risk factor, the HLA-DRB1 gene, to impactexpression of the HLA class II molecules that present antigens to CD4+ T cells. DNAmethylation further affected CD4+ T cells directly through changed epigenetic marking of amicroRNA, miR-21, impacting miR-21 expression and its target genes.Our findings collectively underline the importance of integrating multiple layers of generegulation to identify novel mechanisms involved in the etiology and pathogenesis ofcomplex diseases like MS. This will in turn open up for novel therapeutic approaches basedon targeting dysregulated epigenomes in human disease.