Genetic and epigenetic factors shaping the transcriptome in multiple sclerosis and its animal model
Abstract: Multiple Sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system. Susceptibility to develop MS is determined by both genetic and environmental factors. The epigenome resides in the interface of genetic and environmental factors thereby shaping the transcriptome. Furthermore, epigenetic mechanisms have been implicated in the etiology of MS. Epigenetics refers to changes in gene expression that are not a result of alterations in DNA sequence. Epigenetic mechanisms include histone modifications, DNA methylation and non-coding RNAs. MicroRNAs (miRNAs), small non-coding RNAs known to regulate gene expression, have been found dysregulated in most diseases, including MS. This thesis utilizes an animal model of MS, experimental autoimmune encephalomyelitis (EAE), to investigate epigenetic mechanisms and miRNAs as mediators and modulators of autoimmunity. Through the use of a knockout mouse model we demonstrated that histone demethylase Kdm3a is not a ‘master regulator’ of EAE. However, we demonstrated that a genetic variant in the rat Kdm3a affects nucleotide secondary structure and potentially protein translation. The role of epigenetic mechanisms was demonstrated by the identification of parent-of-origin dependent effects (such as genomic imprinting) in the inheritance of EAE. Using next generation sequencing we established a miRNA profile that associates with pathogenic immune activation in rat EAE, with potential miRNA-depended regulation of several important functions in the development of autoimmunity. Furthermore, by investigating the potential of circulating miRNAs as biomarkers of MS, we identified miR-150 as a putative novel biomarker for MS in the cerebrospinal fluid. Collectively, we show that modulation of the transcriptome by epigenetic mechanisms and miRNAs can explain more of the unknown underlying factors regulating susceptibility to autoimmune diseases and that dysregulated miRNAs can serve as markers of ongoing pathogenesis
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