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

Xu，Hao ming1; Xu，Jing1; Yang，Mei feng2; Liang，Yu jie3; Peng，Quan zhou4; Zhang，Yuan5; Tian，Cheng mei6; Nie，Yu qiang1; Wang，Li sheng7; Yao，Jun7; Li，De feng7

2022-12-01

10.1186/s12967-022-03477-6

Journal of Translational Medicine   Impact Factor & Quartile

1479-5876

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 CD4T cells (FCM, IF: P = 0.0240, P = 0.0003) and repress the differentiation of double-positive CD4CD8T (DP CD4CD8T) cells (FCM, IF: P = 0.0247, P = 0.0118), contributing to the production of inflammatory cytokines, such as TNF-α (P = 0.0005, P = 0.0005), IL-17 (P = 0.0014, P = 0.0381), and IFN-γ (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 CD4T cells and repressed the differentiation of DP CD4CD8 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.

Colitis model DNA methylation Ulcerative colitis Zbtb7b

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English

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WOS:000817302500005

2-s2.0-85132960820

Scopus

1.Department of Gastroenterology and Hepatology,Guangzhou Digestive Disease Center,Guangzhou First People’s Hospital,School of Medicine,South China University of Technology,Guangzhou,Yuexiu District, No. 1, Panfu Road, Guangdong,510180,China
2.Department of Hematology,Yantian District People’s Hospital,Shenzhen,Guangdong,518020,China
3.Shenzhen Kangning Hospital,Shenzhen,Guangdong,518020,China
4.Department of Pathology,Shenzhen People’s Hospital (The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,Guangdong,518020,China
5.Department of Medical Administration,Huizhou Institute of Occupational Diseases Control and Prevention,Huizhou,Guangdong,516000,China
6.Department of Emergency,Shenzhen People’s Hospital (The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,Guangdong,518020,China
7.Department of Gastroenterology,Shenzhen People’s Hospital (The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology),Luohu District,Shenzhen,No. 1017, Dongmen North Road, Guangdong,518020,China

Xu，Hao ming,Xu，Jing,Yang，Mei feng,et al. Epigenetic DNA methylation of Zbtb7b regulates the population of double-positive CD4+CD8+ T cells in ulcerative colitis[J]. Journal of Translational Medicine,2022,20(1).

Xu，Hao ming.,Xu，Jing.,Yang，Mei feng.,Liang，Yu jie.,Peng，Quan zhou.,...&Li，De feng.(2022).Epigenetic DNA methylation of Zbtb7b regulates the population of double-positive CD4+CD8+ T cells in ulcerative colitis.Journal of Translational Medicine,20(1).

Xu，Hao ming,et al."Epigenetic DNA methylation of Zbtb7b regulates the population of double-positive CD4+CD8+ T cells in ulcerative colitis".Journal of Translational Medicine 20.1(2022).