ABSTRACT In many biological processes the regulation of gene expression involves epigenetic mechanisms. These epigenetic mechanisms depend on reversible chemical modifications of DNA and proteins that can dynamically regulate gene expression. RNA epigenetics is emerging as a new realm of biological regulation. This proposal focuses on the severe autoimmunity that develops in mice when RNA methylation is defective in regulatory T cells, providing a new layer of regulation for regulatory T cell (Treg) function. Although many RNA modifications have been identified, most previous studies focused on modifications of rRNA and tRNA because of their high abundance, large chemical diversity, and functional importance in translation. Modifications are also present in mRNA in eukaryotes, such as the 5' caps of mRNA. N6-methyl-adenosine (m6A) is the most prevalent internal modification in eukaryotic mRNA. However, its biological significance has long been elusive. Recent discoveries of enzymes that are responsible for reversible m6A modification of mRNA have revived the interest and excitement in understanding the biological function of the m6A modification. We have developed a conditional knockout mouse for m6A-methyltransferases Mettl14, which represents the ?writer? enzyme that adds the m6A modification. This mouse strain allowed us to dissect the function of m6A modification in a cell-specific manner. Treg cells are indispensible in the homeostasis of the immune system. Perturbations of Treg cell differentiation and function results in autoimmune diseases and immunopathology. Even though Treg lineage commitment and function are controlled by genetic and epigenetic programs, they are also modulated by transcriptional programs responding to various extracellular signals such as TCR stimulation, co-stimulatory and co-inhibitory molecules, and cytokines. The precise activity and mechanism by which the elaborate network of transcription factors modulate Foxp3-dependent functional program in Treg cells remain to be elucidated. Here we show that Treg specific deletion of the Mettl14 gene resulted in severe autoimmune disease similar to Foxp3-deficient mice, but without the loss of Treg cells, suggesting that Treg cell function is impaired. We hypothesize that m6A regulates Treg cell function by modulating mRNA levels and transcriptional program in Treg cells. Our goal is to understand the transcription network underlying proper function of Treg cells.

R21AI128469

2016-12-01

2018-11-30