Abstract
Ulcerative colitis (UC) pathogenesis is related to imbalance of immune responses, and the equilibrium between inflammatory T cells and Foxp3+ regulatory T cells (Tregs) plays an important role in the intestinal homeostasis. Protein arginine methyltransferases (PRMTs) regulate chromatin remodeling and gene expression. Here, we investigated whether inhibition of PRMTs affects colitis pathogenesis in mice and inflammatory bowel disease patients and further explored the underlying mechanisms. In this study, we found that protein arginine N-methyltransferase inhibitor 1 (AMI-1) treatments increased Tregs frequency, function, and reduced colitis incidence. Adoptive transfer of AMI-1-treated Tregs could reduce the colitis incidence. Colitis was associated with increased local PRMT5 expression, which was inhibited by AMI-1 treatment. Additionally, PRMT5 knockdown T cells produced a better response to TGFβ and promoted Tregs differentiation through decreased DNA methyltransferase 1 (DNMT1) expression. PRMT5 also enhanced H3K27me3 and DNMT1 binding to Foxp3 promoter, which restricted Tregs differentiation. Furthermore, PRMT5 knockdown led to decreased Foxp3 promoter methylation during Tregs induction. PRMT5 expression had a negative relationship with Tregs in UC patients, knockdown of PRMT5 expression increased Tregs frequency and decreased TNFα, IL-6, and IL-13 levels. Our study outlines a novel regulation of PRMT5 on Tregs development and function. Strategies to decrease PRMT5 expression might have therapeutic potential to control UC.
Highlights
Protein arginine methyltransferases (PRMTs) are involved in posttranslational modification that can methylate arginine residues on histone and non-histone proteins, and this common modification has been engaged in protein trafficking, gene transcription, and tumor growth [1, 2]
Consistent with previous reports, we found that the Tregs number were deficient in the Ulcerative colitis (UC) patients (Figure 7B), and the PRMT5 expression level was negatively correlated with the Foxp3 expression level in the patients (Figure 7C)
We showed that arginine N-methyltransferase inhibitor 1 (AMI-1) administration increased the frequency of peripheral Foxp3+ Tregs and increased their suppressive capability
Summary
Protein arginine methyltransferases (PRMTs) are involved in posttranslational modification that can methylate arginine residues on histone and non-histone proteins, and this common modification has been engaged in protein trafficking, gene transcription, and tumor growth [1, 2]. PRMT5 Inhibition Promotes Tregs Frequency and Function in UC gene transcription profiles in T helper lymphocytes. Inhibition of arginine methylation impaired type 1 and type 2 helper cytokine expression levels, including IFNγ, IL-4, and IL-2 [5, 6]. Several small-molecule PRMT inhibitors have been synthesized, such as C21 [7]. Protein arginine N-methyltransferase inhibitor 1 (AMI-1) inhibits arginine methyltransferase activity and does not inhibit lysine methyltransferase activity [8]. AMI-1 was reported that inhibits PRMT5 activity inhibits colorectal cancer growth by decreasing arginine methylation of eIF4E and FGFR3 [9]. A full understanding of the functional role of AMI-1 in the regulation of Tregs functioning during intestinal inflammation remains unclear
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