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.
Department of Hematology, Yantian District People's Hospital, Shenzhen, 518020, Guangdong, China.
J Transl Med. 2022 Jun 27;20(1):289. doi: 10.1186/s12967-022-03477-6.
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.
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.
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.
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.
溃疡性结肠炎（UC）是一种具有复杂发病机制的异质性疾病。因此，本研究旨在评估与 UC 发病机制明确相关的全基因组 DNA 甲基化变化。
通过比较 GEO 数据库中的 UC 组织与健康对照（HC），确定 DNA 甲基化变化。在临床样本中获得并验证候选基因。此外，使用葡聚糖硫酸钠（DSS）诱导的结肠炎模型探索与 UC 发病机制相关的 Zbtb7b 潜在分子机制。
来自 GEO 数据库的生物信息学分析证实，已知的 Th 诱导 POZ-Kruppel 因子（ThPOK）Zbtb7b 在 UC 组织中被去甲基化。然后，我们通过 DSS 诱导的结肠炎模型证明 Zbtb7b 呈低甲基化模式（P=0.0357），而 Zbtb7b 在 UC 患者炎症性结肠组织中的 mRNA 和蛋白水平表达显著上调（qRT-PCR、WB、IHC：P<0.0001、P=0.0079、P<0.0001）和 DSS 诱导的结肠炎模型（qRT-PCR、WB、IHC：P<0.0001、P=0.0045、P=0.0004）。此外，Zbtb7b 的表达与 UC 活动程度呈正相关。在机制上，Zbtb7b 的过表达可能会激活 CD4T 细胞的成熟（FCM、IF：P=0.0240、P=0.0003），并抑制双阳性 CD4CD8T（DP CD4CD8T）细胞的分化（FCM、IF：P=0.0247、P=0.0118），导致 TNF-α（P=0.0005、P=0.0005）、IL-17（P=0.0014、P=0.0381）和 IFN-γ（P=0.0016、P=0.0042）等炎症细胞因子在 DSS 诱导的结肠炎模型血清和结肠组织中的产生。
Zbtb7b 的表观遗传 DNA 低甲基化激活了 CD4T 细胞的成熟，并抑制了 DP CD4CD8 T 细胞的分化，导致炎症细胞因子的产生和 UC 中的结肠炎症。因此，Zbtb7b 可能是 UC 的诊断和治疗生物标志物，低甲基化可能影响 Zbtb7b 的生物学功能。
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