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

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory and neurodegenerative disease driven by autoreactive CD4+ T cells. Disease etiology is mediated by a strong interplay between genetic and environmental factors implying a role for epigenetic mechanisms. Epigenetics is defined as the study of mechanisms, such as DNA methylation, histone modifications and non-coding RNAs, 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 to be expressed only from the maternally or paternally inherited chromosome.

In this thesis we investigate the contribution of epigenetic mechanisms to the etiology and pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE). We investigated the impact of parent-of-origin, in particular genomic imprinting, using two large populations of reciprocal backcross rats and identified that epigenetic mechanisms play a role in EAE inheritance and pathogenesis. Using a transgenic mouse model, we discovered that the imprinted Dlk1 gene impacts the underlying immune responses in EAE. Further discovery of imprinted genes, using RNA sequencing in adult reciprocal hybrid rats, provided additional insights into the underlying mechanisms of how imprinted genes could interfere with the immune response in EAE by modulating CD4+ T cell function.

Utilizing a genome-wide approach to identify DNA methylation changes between MS patients and controls in CD4+ T cells and monocytes revealed how DNA methylation as an epigenetic mark can impact the function of CD4+ T cells in MS. We identified that DNA methylation acts as a mediator of the major MS risk factor, the HLA-DRB1 gene, to impact expression of the HLA class II molecules that present antigens to CD4+ T cells. DNA methylation further affected CD4+ T cells directly through changed epigenetic marking of a microRNA, miR-21, impacting miR-21 expression and its target genes.

Our findings collectively underline the importance of integrating multiple layers of gene regulation to identify novel mechanisms involved in the etiology and pathogenesis of complex diseases like MS. This will in turn open up for novel therapeutic approaches based on targeting dysregulated epigenomes in human disease.