Abstract
Epigenetic modifications have been shown to be important for immune cell differentiation by regulating gene transcription. However, the role and mechanism of histone methylation in the development and differentiation of iNKT cells in rheumatoid arthritis (RA) mice have yet to be deciphered. The DBA/1 mouse RA model was established by using a modified GPI mixed peptide. We demonstrated that total peripheral blood, thymus, and spleen iNKT cells in RA mice decreased significantly, while iNKT1 in the thymus and spleen was increased significantly. PLZF protein and PLZF mRNA levels were significantly decreased in thymus DP T cells, while T-bet protein and mRNA were significantly increased in thymus iNKT cells. We found a marked accumulation in H3K27me3 around the promoter regions of the signature gene Zbtb16 in RA mice thymus DP T cells, and an accumulation of H3K4me3 around the promoters of the Tbx21 gene in iNKT cells. The expression levels of UTX in the thymus of RA mice were significantly reduced. The changes in the above indicators were particularly significant in the progressive phase of inflammation (11 days after modeling) and the peak phase of inflammation (14 days after modeling) in RA mice. Developmental and differentiation defects of iNKT cells in RA mice were associated with abnormal methylation levels (H3K27me3 and H3K4me3) in the promoters of key genes Zbtb16 (encoding PLZF) and Tbx21 (encoding T-bet). Decreased UTX of thymus histone demethylase levels resulted in the accumulation of H3K27me3 modification.
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (NSFC) (81771755), Colleges and University’s Science and Technology Key Research Project of Hebei Province (ZD2017009), the Animal Lab of Medical Experiment Center of Hebei University, and Key Laboratory of Pathogenesis mechanism and control of inflammatory-autoimmune diseases in Hebei Province.
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All experiments were approved by the Animal Welfare and Ethical Committee of Hebei University (approval number IACUC-2017009).
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Highlights
• The decrease of iNKT cells and the imbalance of subsets in RA are related to the abnormal development and differentiation of iNKT.
• Developmental and differentiation defects of iNKT cells in RA mice were associated with abnormal methylation levels of key genes Zbtb16 and Tbx21 promoters H3K27me3 and H3K4me3.
• Decreased UTX of thymus histone demethylase resulted in the accumulation of H3K27me3 modification.
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Meng, M., Liu, H., Chen, S. et al. Methylation of H3K27 and H3K4 in key gene promoter regions of thymus in RA mice is involved in the abnormal development and differentiation of iNKT cells. Immunogenetics 71, 489–499 (2019). https://doi.org/10.1007/s00251-019-01124-x
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DOI: https://doi.org/10.1007/s00251-019-01124-x