Epigenetic DNA methylation of Zbtb7b regulates the population of double-positive CD4+CD8+ T cells in ulcerative colitis

被引:7
作者
Xu, Hao-ming [1 ]
Xu, Jing [1 ]
Yang, Mei-feng [2 ]
Liang, Yu-jie [3 ]
Peng, Quan-zhou [4 ]
Zhang, Yuan [5 ]
Tian, Cheng-mei [6 ]
Nie, Yu-qiang [1 ]
Wang, Li-sheng [7 ]
Yao, Jun [7 ]
Li, De-feng [7 ]
机构
[1] South China Univ Technol, Sch Med, Guangzhou Peoples Hosp 1, Dept Gastroenterol & Hepatol,Guangzhou Digest Dis, 1,Panfu Rd, Guangzhou 510180, Guangdong, Peoples R China
[2] Yantian Dist Peoples Hosp, Dept Hematol, Shenzhen 518020, Guangdong, Peoples R China
[3] Shenzhen Kangning Hosp, Shenzhen 518020, Guangdong, Peoples R China
[4] Jinan Univ, Shenzhen Peoples Hosp, Dept Pathol, Southern Univ Sci & Technol,Affiliated Hosp 1, Shenzhen 518020, Guangdong, Peoples R China
[5] Huizhou Inst Occupat Dis Control & Prevent, Dept Med Adm, Huizhou 516000, Guangdong, Peoples R China
[6] Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen Peoples Hosp, Dept Emergency,Jinan Univ,Clin Med Coll 2, Shenzhen 518020, Guangdong, Peoples R China
[7] Jinan Univ, Dept Gastroenterol, Shenzhen Peoples Hosp, Southern Univ Sci & Technol,Affiliated Hosp 1, 1017,Dongmen North Rd, Shenzhen 518020, Guangdong, Peoples R China
基金
中国国家自然科学基金;
关键词
Ulcerative colitis; Zbtb7b; DNA methylation; Colitis model; INFLAMMATORY-BOWEL-DISEASE; COLORECTAL-CANCER; THPOK; EXPRESSION; INHIBITION; GENES; CD4;
D O I
10.1186/s12967-022-03477-6
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Background and aims Ulcerative colitis (UC) is a heterogeneous disorder with complex pathogenesis. Therefore, in the present study, we aimed to assess genome-wide DNA methylation changes associated explicitly with the pathogenesis of UC. Methods DNA methylation changes were identified by comparing UC tissues with healthy controls (HCs) from the GEO databases. The candidate genes were obtained and verified in clinical samples. Moreover, the underlying molecular mechanism related to Zbtb7b in the pathogenesis of UC was explored using the dextran sodium sulfate (DSS)-induced colitis model. Results Bioinformatic analysis from GEO databases confirmed that Zbtb7b, known as Th-inducing POZ-Kruppel factor (ThPOK), was demethylated in UC tissues. Then, we demonstrated that Zbtb7b was in a hypo-methylation pattern through the DSS-induced colitis model (P = 0.0357), whereas the expression of Zbtb7b at the mRNA and protein levels was significantly up-regulated in the inflamed colonic tissues of UC patients (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0079, P < 0.0001) and DSS-induced colitis model (qRT-PCR, WB, IHC: P < 0.0001, P = 0.0045, P = 0.0004). Moreover, the expression of Zbtb7b was positively associated with the degree of UC activity. Mechanically, over-expression of Zbtb7b might activate the maturation of CD4(+)T cells (FCM, IF: P = 0.0240, P = 0.0003) and repress the differentiation of double-positive CD4(+)CD8(+)T (DP CD4(+)CD8(+)T) cells (FCM, IF: P = 0.0247, P = 0.0118), contributing to the production of inflammatory cytokines, such as TNF-alpha (P = 0.0005, P = 0.0005), IL-17 (P = 0.0014, P = 0.0381), and IFN-gamma (P = 0.0016, P = 0.0042), in the serum and colonic tissue of DSS-induced colitis model. Conclusions Epigenetic DNA hypo-methylation of Zbtb7b activated the maturation of CD4(+)T cells and repressed the differentiation of DP CD4(+)CD8(+) T cells, resulting in the production of inflammatory cytokines and colonic inflammation in UC. Therefore, Zbtb7b might be a diagnostic and therapeutic biomarker for UC, and hypo-methylation might affect the biological function of Zbtb7b.
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页数:15
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