Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, PR China; Key Laboratory of Zoonosis of the Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou 510642, Guangdong, PR China.
Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, College of Life Sciences, South China Agricultural University, Guangzhou 510642, Guangdong, PR China; Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou 510642, Guangdong, PR China; Key Laboratory of Zoonosis of the Ministry of Agriculture and Rural Affairs, South China Agricultural University, Guangzhou 510642, Guangdong, PR China.
Biochem Pharmacol. 2023 May;211:115506. doi: 10.1016/j.bcp.2023.115506. Epub 2023 Mar 21.
T-2 toxin is a hazardous environmental pollutant that poses a risk to both farm animals and humans. Our previous research has reported that T-2 toxin highly induced the expression of human cytochrome P450 1A1 (CYP1A1), which may be a representative inducible marker of T-2 toxin and mediate the toxicity of T-2 toxin. In this study, we found that T-2 toxin decreased the DNA methylation levels of the CpG islands on the CYP1A1 promoter by inducing the expression of eleven translocation family protein 3 (TET3) and facilitating its binding to the promoter. These DNA methylation changes then generated an activated chromatin structure on the CYP1A1 promoter by releasing the repressor complex methyl-binding protein 2 (MeCP2) and histone deacetylase 2 (HDAC2), increasing the active histone modification markers, including H3K4ac, H3K9ac and H3K14ac, and facilitating RNA pol II and NRF1/Sp1 recruitment, which ultimately led to the transcriptional activation of CYP1A1. Interestingly, TET3-mediated CYP1A1 induction enhanced the cytotoxicity of T-2 toxin through inhibiting cell proliferation. Our results demonstrate that T-2 toxin-induced CYP1A1 expression is detrimental to cells and clearly show how T-2 toxin inhibits cell proliferation through regulating CYP1A1 expression from an epigenetic perspective. The findings broaden our current knowledge of the epigenetic mechanisms regulating environmental factors-induced CYP1A1 expression and cytotoxicity. TET3 may serve as a potential new target for toxicogenic detoxification.
T-2 毒素是一种有害的环境污染物，对农场动物和人类都构成威胁。我们之前的研究报告称，T-2 毒素能高度诱导人细胞色素 P4501A1（CYP1A1）的表达，这可能是 T-2 毒素的代表性诱导标志物，并介导 T-2 毒素的毒性。在这项研究中，我们发现 T-2 毒素通过诱导十一转移家族蛋白 3（TET3）的表达并促进其与启动子结合，降低 CYP1A1 启动子上 CpG 岛的 DNA 甲基化水平。这些 DNA 甲基化变化通过释放抑制复合物甲基结合蛋白 2（MeCP2）和组蛋白去乙酰化酶 2（HDAC2），在 CYP1A1 启动子上产生激活的染色质结构，增加包括 H3K4ac、H3K9ac 和 H3K14ac 在内的活性组蛋白修饰标记物，促进 RNA pol II 和 NRF1/Sp1 的募集，从而最终导致 CYP1A1 的转录激活。有趣的是，TET3 介导的 CYP1A1 诱导通过抑制细胞增殖增强了 T-2 毒素的细胞毒性。我们的结果表明，T-2 毒素诱导的 CYP1A1 表达对细胞有害，并从表观遗传学角度清楚地表明 T-2 毒素如何通过调节 CYP1A1 表达来抑制细胞增殖。这些发现拓宽了我们对调节环境因素诱导 CYP1A1 表达和细胞毒性的表观遗传机制的现有认识。TET3 可能成为一种有潜力的新的解毒靶点。
