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The Role of H3K27me3-Mediated Th17 Differentiation in Ankylosing Spondylitis

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Abstract

Ankylosing spondylitis (AS) is a common chronic progressive inflammatory autoimmune disease. T helper 17 (Th17) cells are the major effector cells mediating AS inflammation. Histone 3 Lys 27 trimethylation (H3K27me3) is an inhibitory histone modification that silences gene transcription and plays an important role in Th17 differentiation. The objective of this study was to investigate the expression of H3K27me3 in patients with AS and to explore its epigenetic regulation mechanism of Th17 differentiation during AS inflammation. We collected serum samples from 45 patients with AS at various stages and 10 healthy controls to measure their Interleukin-17 (IL-17) levels using ELISA. A quantitative polymerase chain reaction was used to quantify the mRNA levels of RORc and the signaling molecules of the JAK2/STAT3 pathway, JMJD3, and EZH2. Additionally, Western blot analysis was performed to quantify the protein levels of H3K27me3, RORγt, JAK2, STAT3, JMJD3, and EZH2 in cell protein extracts. The results showed that H3K27me3 expression in peripheral blood mononuclear cells (PBMCs) was significantly lower in patients with active AS compared to both the normal control groups and those with stable AS. Moreover, a significant negative correlation was observed between H3K27me3 expression and the characteristic transcription factor of Th17 differentiation, RORγt. We also discovered that patients with active AS exhibited significantly higher levels of JMJD3, an inhibitor of H3K27 demethylase, compared to the normal control group and patients with stable AS, while the expression of H3K27 methyltransferase (EZH2) was significantly lower. These findings suggest that H3K27me3 may be a dynamic and important epigenetic modification in AS inflammation, and JMJD3/EZH2 regulates the methylation level of H3K27me3, which may be one of the key regulatory factors in the pathogenesis of AS. These findings contribute to our understanding of the role of epigenetics in AS and may have implications for the development of novel therapeutic strategies for AS.

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Acknowledgements

We thank the Stem Cell Center and the Medical Molecular Biology Laboratory of Peking University Health Science Center for their technical support. We also thank the Department of Laboratory Medicine of Guang’anmen Hospital for assistance with ESR and CRP testing.

Funding

This work was supported by the National Natural Science Foundation of China (no. 81873292), the Beijing Municipal Natural Science Foundation (no. 7212190), and the Major Tackling Project of Science and Technology Innovation Project of the Chinese Academy of Traditional Chinese Medicine (no.CI2021A01506).

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Author notes

  1. Yuening Chen, Wanlin Liu, and Xiaohan Xu contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology, China Academy of Chinese Medical Sciences, Guang’anmen Hospital, Beijing, 100053, China

    Yuening Chen, Zhe Zhao, Yanan Zhao & Hongxiao Liu

  2. State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, 102206, China

    Wanlin Liu

  3. Department of Cell Biology, Basic Medical School, Peking University Health Science Center, Beijing, 100191, China

    Hongying Zhen

  4. Clinical Laboratory, China Academy of Chinese Medical Sciences, Guang’anmen Hospital, Beijing, 100053, China

    Bo Pang

  5. Guang’anmen Hospital Jinan, China Academy of Chinese Medical Sciences, Jinan, 250012, China

    Xiaohan Xu

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  1. Yuening Chen
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Contributions

Hongxiao Liu conceived and supervised the study. Yuening Chen, Wanlin Liu, and Xiaohan Xu performed the literature review and drafted the manuscript. Bo Pang and Yanan Zhao contributed to experimental data collection and analysis. Yuening Chen, Wanlin Liu, Xiaohan Xu, and Zhe Zhao prepared the figures. Hongxiao Liu and Hongying Zhen contributed to the critical revision of the manuscript. All authors approved the final manuscript and agreed to take responsibility for all aspects of the work.

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Correspondence to Hongxiao Liu.

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The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of Guang’anmen Hospital, China Academy of Chinese Medical Sciences (no. 2022–108-KY). All subjects provided written informed consent prior to the study.

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Chen, Y., Liu, W., Xu, X. et al. The Role of H3K27me3-Mediated Th17 Differentiation in Ankylosing Spondylitis. Inflammation (2024). https://doi.org/10.1007/s10753-024-02002-9

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