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Tytuł:
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Epigenetic DNA methylation of Zbtb7b regulates the population of double-positive CD4 T cells in ulcerative colitis.
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Autorzy:
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Xu HM; Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Yuexiu District, No. 1, Panfu Road, Guangzhou, 510180, Guangdong, China.
Xu J; Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Yuexiu District, No. 1, Panfu Road, Guangzhou, 510180, Guangdong, China.
Yang MF; Department of Hematology, Yantian District People's Hospital, Shenzhen, 518020, Guangdong, China.
Liang YJ; Shenzhen Kangning Hospital, Shenzhen, 518020, Guangdong, China.
Peng QZ; 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, 518020, Guangdong, China.
Zhang Y; Department of Medical Administration, Huizhou Institute of Occupational Diseases Control and Prevention, Huizhou, 516000, Guangdong, China.
Tian CM; 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, 518020, Guangdong, China.
Nie YQ; Department of Gastroenterology and Hepatology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Yuexiu District, No. 1, Panfu Road, Guangzhou, 510180, Guangdong, China. .
Wang LS; 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, No. 1017, Dongmen North Road, Shenzhen, 518020, Guangdong, China. .
Yao J; 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, No. 1017, Dongmen North Road, Shenzhen, 518020, Guangdong, China. .
Li DF; 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, No. 1017, Dongmen North Road, Shenzhen, 518020, Guangdong, China. .
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Źródło:
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Journal of translational medicine [J Transl Med] 2022 Jun 27; Vol. 20 (1), pp. 289. Date of Electronic Publication: 2022 Jun 27.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Original Publication: [London] : BioMed Central, 2003-
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MeSH Terms:
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CD4-Positive T-Lymphocytes*/metabolism
CD8-Positive T-Lymphocytes*/metabolism
Colitis, Ulcerative*/genetics
DNA-Binding Proteins*/genetics
DNA-Binding Proteins*/metabolism
Epigenesis, Genetic*
Transcription Factors*/genetics
Transcription Factors*/metabolism
Animals ; Colitis/chemically induced ; Colitis/genetics ; Colon/pathology ; Cytokines/metabolism ; DNA Methylation ; Dextran Sulfate/adverse effects ; Dextran Sulfate/metabolism ; Humans ; Mice ; Mice, Inbred C57BL
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References:
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Contributed Indexing:
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Keywords: Colitis model; DNA methylation; Ulcerative colitis; Zbtb7b
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Substance Nomenclature:
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0 (Cytokines)
0 (DNA-Binding Proteins)
0 (Transcription Factors)
0 (ZBTB7B protein, human)
0 (Zbtb7b protein, mouse)
9042-14-2 (Dextran Sulfate)
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Entry Date(s):
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Date Created: 20220627 Date Completed: 20220629 Latest Revision: 20220716
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Update Code:
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20240105
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PubMed Central ID:
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PMC9235105
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DOI:
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10.1186/s12967-022-03477-6
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PMID:
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35761286
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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-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 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.
(© 2022. The Author(s).)
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