DNA甲基化异常在结直肠癌（CRC）中很常见，但其潜在机制和病理后果尚不清楚。我们从ApcMin小鼠中破坏了活性DNA去甲基化基因Tet1和/或Tdg，以及表征结肠腺瘤的甲基组和转录组数据。将数据与TCGA中的人类结肠腺癌（COAD）进行比较。表达TdgN151A等位基因的ApcMin小鼠小肠腺瘤数量增加，而Tet1缺陷和Tet1 / TdgN151A双杂合子ApcMin结肠腺瘤则更大，具有侵蚀和侵袭特性。在Tet1和Tdg突变ApcMin小鼠的结肠腺瘤中，全局DNA低甲基化减少，CpG岛高甲基化； TET1和Tdg突变结肠腺瘤中，炎症、免疫和干扰素反应基因的上调与对照ApcMin腺瘤相比更显着。这种上调在小鼠结肠的有机体和感染表达TET1或TDG shRNA的人类CRC细胞系中也有出现。一个127基因的炎症特征分离COAD四个组，与微卫星或染色体不稳定性紧密相关，并由不同水平的DNA甲基化和DNMT1表达描述，这与TET1表达反相关。 CIMP（CpG岛甲基转移酶表型）的肿瘤具有协调的高DNMT1 /低TET1表达。在CRC细胞系中敲低TET1或TDG会增强NK细胞的杀伤作用。我们的发现揭示了一种新的表观遗传调节，与基因组不稳定类型相关，在TET1-TDG介导的DNA去甲基化过程中降低甲基化水平和炎症/干扰素/免疫反应。 CRC中的CIMP是由甲基化活性不足引起的。这些小鼠代表了CIMP CRC的一个模型。版权所有2023年AGA研究所。由Elsevier Inc.发表，版权所有。

Aberrant DNA methylation is frequent in colorectal cancer (CRC), but underlying mechanisms and pathological consequences are poorly understood.We disrupted active DNA demethylation genes Tet1 and/or Tdg from ApcMin mice, and characterized the methylome and transcriptome of colonic adenomas. Data were compared to human colonic adenocarcinomas (COAD) in TCGA.There were increased numbers of small intestinal adenomas in ApcMin mice expressing the TdgN151A allele, whereas Tet1-deficient and Tet1/TdgN151A-double heterozygous ApcMin colonic adenomas were larger with features of erosion and invasion. We detected reduction in global DNA hypomethylation in colonic adenomas from Tet1- and Tdg-mutant ApcMin mice, and hypermethylation of CpG islands in Tet1-mutant ApcMin adenomas. Upregulation of inflammatory, immune and interferon response genes was present in Tet1- and Tdg-mutant colonic adenomas compared to control ApcMin adenomas. This upregulation was also seen in murine colonic organoids and human CRC lines infected with lentiviruses expressing TET1 or TDG shRNA. A 127-gene inflammatory signature separated COAD into four groups, closely aligned with their microsatellite or chromosomal instability, and characterized by different levels of DNA methylation and DNMT1 expression that anti-correlated with TET1 expression. Tumors with the CpG island methylator phenotype (CIMP) had concerted high DNMT1/low TET1 expression. TET1 or TDG knockdown in CRC lines enhanced killing by NK cells.Our findings reveal a novel epigenetic regulation, linked to the type of genomic instability, by which TET1-TDG-mediated DNA demethylation decreases methylation levels and inflammatory/interferon/immune responses. CIMP in CRC is triggered by an imbalance of methylating activities over demethylating activities. These mice represent a model of CIMP CRC.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.