Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.
Gene. 2010 Feb 15;452(1):16-21. doi: 10.1016/j.gene.2009.12.002. Epub 2009 Dec 21.
Human arylamine N-acetyltransferase 1 (NAT1), a polymorphic xenobiotic metabolising enzyme, has been investigated in relation to susceptibility and prognosis in certain types of cancer. Both human NAT1 and its murine equivalent NAT2 have previously been shown to play roles in the catabolism of folate, which is required for the synthesis of S-adenosylmethionine, the methyl donor for cellular methylation reactions. We have tested whether the expression of mouse Nat2 is subject to epigenetic regulation, specifically CpG methylation in the promoter region, by determining levels of 5-methylcytosine by bisulphite sequencing and methylation-specific PCR. Under normal conditions, methylation levels of the Nat2 promoter were low, and varied in different tissues. However, CpG methylation was significantly increased by dietary folate supplementation, and increased methylation corresponded to decreased use of the core promoter. Functional deletion of the Nat2 gene gave rise to a significant increase in Nat2 methylation, extending our previous observations that folate catabolism is decreased in Nat2 null mice. Mouse NAT2 is likely to influence epigenetic gene control, particularly of its own locus, and this is consistent with recent evidence associating aberrant mouse Nat2/human NAT1 gene expression with certain developmental malformations and cancers.
人类芳香胺 N-乙酰基转移酶 1（NAT1）是一种多态性的外来化合物代谢酶，与某些类型癌症的易感性和预后有关。人类 NAT1 和其对应的鼠源 NAT2 先前已被证明在叶酸代谢中发挥作用，叶酸是合成 S-腺苷甲硫氨酸（细胞甲基化反应的甲基供体）所必需的。我们通过亚硫酸氢盐测序和甲基化特异性 PCR 来测定 5-甲基胞嘧啶的水平，以测试鼠源 Nat2 的表达是否受到表观遗传调控，特别是启动子区域的 CpG 甲基化。在正常情况下，Nat2 启动子的甲基化水平较低，并且在不同组织中存在差异。然而，膳食叶酸补充显著增加了 Nat2 启动子的甲基化，增加的甲基化对应于核心启动子使用的减少。Nat2 基因的功能缺失导致 Nat2 甲基化显著增加，这扩展了我们先前的观察结果，即 Nat2 缺失小鼠中的叶酸代谢减少。鼠源 NAT2 可能会影响表观遗传基因控制，特别是其自身基因座的控制，这与最近的证据一致，该证据表明异常的鼠源 Nat2/人类 NAT1 基因表达与某些发育畸形和癌症有关。
