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HMGB1 Recruits TET2/AID/TDG to Induce DNA Demethylation in STAT3 Promoter in CD4+ T Cells from aGVHD Patients
Journal of Immunology Research ( IF 3.5 ) Pub Date : 2020-09-24 , DOI: 10.1155/2020/7165230
Xuejun Xu 1 , Yan Chen 1 , Enyi Liu 1 , Bin Fu 1 , Juan Hua 1 , Xu Chen 1 , Yajing Xu 1
Affiliation  

STAT3 is highly expressed in aGVHD CD4+ T cells and plays a critical role in inducing or worsening aGVHD. In our preceding studies, DNA hypomethylation in STAT3 promoter was shown to cause high expression of STAT3 in aGVHD CD4+ T cells, and the process could be modulated by HMGB1, but the underlying mechanism remains unclear. TET2, AID, and TDG are indispensable in DNA demethylation; meanwhile, TET2 and AID also serve extremely important roles in immune response. So, we speculated these enzymes involved in the STAT3 promoter hypomethylation induced by HMGB1 in aGVHD CD4+ T cells. In this study, we found that the binding levels of TET2/AID/TDG to STAT3 promoter were remarkably increased in CD4+T cells from aGVHD patients and were significantly negatively correlated with the STAT3 promoter methylation level. Simultaneously, we revealed that HMGB1 could recruit TET2, AID, and TDG to form a complex in the STAT3 promoter region. Interference with the expression of TET2/AID/TDG inhibited the overexpression of STAT3 caused by HMGB1 downregulation of the STAT3 promoter DNA methylation. These data demonstrated a new molecular mechanism of how HMGB1 promoted the expression of STAT3 in CD4+ T cells from aGVHD patients.

中文翻译:

HMGB1 招募 TET2/AID/TDG 以诱导来自 aGVHD 患者的 CD4+T 细胞中 STAT3 启动子的 DNA 去甲基化

STAT3 在 aGVHD CD4 + T 细胞中高度表达,并在诱导或恶化 aGVHD 中起关键作用。在我们之前的研究中,STAT3 启动子中的 DNA 低甲基化被证明会导致 aGVHD CD4 + T 细胞中 STAT3 的高表达,并且该过程可以被 HMGB1 调节,但潜在机制尚不清楚。TET2、AID 和 TDG 在 DNA 去甲基化过程中不可或缺;同时,TET2 和 AID 在免疫反应中也发挥着极其重要的作用。因此,我们推测这些酶参与了 HMGB1 在 aGVHD CD4 + T 细胞中诱导的 STAT3 启动子低甲基化。在本研究中,我们发现 TET2/AID/TDG 与 STAT3 启动子的结合水平在 CD4 +来自 aGVHD 患者的 T 细胞与 STAT3 启动子甲基化水平显着负相关。同时,我们发现 HMGB1 可以招募 TET2、AID 和 TDG 在 STAT3 启动子区域形成复合物。干扰TET2/AID/TDG的表达抑制了由HMGB1下调STAT3启动子DNA甲基化引起的STAT3过表达。这些数据证明了HMGB1如何促进aGVHD患者CD4 + T细胞中STAT3表达的新分子机制。
更新日期:2020-09-24
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