Epitranscriptomic regulation in immunity and autoimmune disease

Summary

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Gene expression is regulated at different levels. The rate of gene transcription, genomic stability and expression of noncoding sequences can be regulated by modifications on both deoxyribonucleic acid (DNA) bases and histones. In addition, regulation of expression also occurs at the RNA transcript level. Post-transcriptional, or epitranscriptomic, regulation involving RNA binding proteins and modifications, can determine the turnover and translation rate of mRNA transcripts. Post-transcriptional regulation has been demonstrated to modulate the expression of proteins involved in T cell function such as cytokine and cell surface receptors.

N6-methyladenosine (m6A) is the most abundant and well-studied RNA modification in eukaryotic cells. This modification is known to be involved in the regulation of various molecular mechanisms including immune cell differentiation and function, autoimmune disease pathogenesis and anti-viral immunity. The work described in this thesis is aimed to create more insight into the role of m6A and its regulatory proteins in innate- and adaptive immune cell function, anti-viral immunity against RSV and juvenile idiopathic arthritis pathogenesis.

In this thesis, novel functions of this RNA modification and its regulatory proteins in both innate- and adaptive immune cells have been identified. Evidence was found that CD4+ T cell activation is mediated by m6A. Also, it was demonstrated that m6A modifications modulate TNF expression in both CD4+ T lymphocytes and monocytes. This work describes how m6A is involved in anti-viral immune responses against respiratory syncytial virus (RSV) infection. And finally, it was found that m6A can contribute to juvenile idiopathic arthritis (JIA) pathogenesis. These findings indicate that targeting  m6A regulatory proteins might be of interest for the treatment of autoimmune diseases and viral infections.