TET2-mediated upregulation of 5-hydroxymethylcytosine in LRRC39 promoter promotes Th1 response in association with downregulated Treg response in Vogt-Koyanagi-Harada disease

作者全名："Zhang, Wanyun; Chen, Zhijun; Yi, Kun; Su, Guannan; Liu, Yaning; Deng, Yang; Zhang, Yinan; Cao, Qingfeng; Pu, Yanlin; Luo, Xiang; Lai, Yujie; Yang, Peizeng"

作者地址："[Zhang, Wanyun; Chen, Zhijun; Yi, Kun; Su, Guannan; Liu, Yaning; Deng, Yang; Cao, Qingfeng; Pu, Yanlin; Luo, Xiang; Lai, Yujie; Yang, Peizeng] Chongqing Med Univ, Chongqing Eye Inst, Chongqing Branch,Municipal Div,Natl Clin Res Ctr O, Chongqing Key Lab Ophthalmol,Affiliated Hosp 1, Chongqing, Peoples R China; [Zhang, Yinan] Zhengzhou Univ, Henan Prov Eye Hosp, Dept Ophthalmol,Affiliated Hosp 1, Henan Int Joint Res Lab Ocular Immunol & Retinal I, Zhengzhou, Peoples R China; [Zhang, Yinan] Zhengzhou Univ, Acad Med Sci, Zhengzhou, Peoples R China; [Yang, Peizeng] Chongqing Med Univ, Affiliated Hosp 1, Youyi Rd 1, Chongqing 400016, Peoples R China"

通信作者："Yang, PZ (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Youyi Rd 1, Chongqing 400016, Peoples R China."

来源：CLINICAL IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:000980709200001

JCR分区：Q2

影响因子：4.5

年份：2023

卷号：250

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Autoimmune disease; VKH disease; 5-hmC; Transcriptomics; TET2; LRRC39

摘要："DNA 5-Hydroxymethylcytosine (5-hmC), an oxidative reaction mediated by the ten-eleven translocation (TET) family, has been reported to play an essential role in the progression of auto-inflammatory and autoimmune diseases. By far, little is known about the effect of DNA 5-hmC and the TET family on the development of Vogt-Koyanagi-Harada (VKH) disease. In this study, we discovered that the global DNA 5-hmC level and the TET activity were elevated in association with the up-regulated expression of TET2 at both mRNA and protein levels in CD4+T cells from active VKH patients compared to healthy controls. Integrated analysis of DNA 5-hmC pattern and transcription profile of CD4+ T cells revealed that 6 candidate target genes were involved in the development of VKH disease. The promoter 5-hmC and mRNA levels of leucine rich repeat containing 39 (LRRC39) were verified to be elevated in active VKH patients. Functional experiments showed that TET2 could up-regulate LRRC39 mRNA expression by increasing the promoter 5-hmC level of LRRC39 in CD4+ T cells from active VKH patients. Up-regulated LRRC39 expression could increase the frequencies of IFN-gamma+ and IL-17+ CD4+ T cells as well as the secretions of IFN-gamma and IL-17 in association with the decreased frequency of CD4+CD25+FOXP3+ regulatory T (Treg) cells and the reduced production of IL-10. Additionally, restoration of LRRC39 rescued TET2-silencing-mediated reduced frequency of IFN-gamma+ CD4+ T cells and increased frequency of CD4+CD25+FOXP3+ Treg cells. Collectively, our study reveals a novel axis, the TET2-5-hmC-LRRC39-Th1/Treg responses axis, in the pathogenesis of VKH and provides a potential target for further investigation into the epigenetic therapy of this disease."

基金机构："National Natural Science Foundation Key Program [81930023, 82230032]; Chongqing Outstanding Scientists Project; Chongqing Chief Medical Scientist Project; Key Project of Chongqing Science and Technology Bureau [CSTC2021jscx-gksb- N0010]; Chongqing Key Laboratory of Ophthalmology (CSTC) [2008CA5003]; Chongqing Science & Technology Platform and Base Construction Program [cstc2014pt-sy10002]"

基金资助正文："This study was supported by National Natural Science Foundation Key Program (82230032) , National Natural Science Foundation Key Program (81930023) , Chongqing Outstanding Scientists Project (2019) , the Chongqing Chief Medical Scientist Project (2018) , Key Project of Chongqing Science and Technology Bureau (CSTC2021jscx-gksb- N0010) , Chongqing Key Laboratory of Ophthalmology (CSTC, 2008CA5003) and Chongqing Science & Technology Platform and Base Construction Program (cstc2014pt-sy10002) ."