American Association for Cancer Research
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Supplementary Figure 1 from DNA Hypomethylation Contributes to Genomic Instability and Intestinal Cancer Initiation

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posted on 2023-04-03, 22:10 authored by Karyn L. Sheaffer, Ellen N. Elliott, Klaus H. Kaestner

Supplementary Figure 1. Experimental Schema: Conditional ablation of Dnmt1 in the ApcMin/+ intestinal epithelium ApcMin/+;Dnmt1loxP/loxP mice (controls) and ApcMin/+;Dnmt1loxP/loxP;Villin-Cre-ERT2 mice (mutants) were injected with tamoxifen at 4 weeks of age. Intestines were harvested one week or two months following tamoxifen treatment.

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ARTICLE ABSTRACT

Intestinal cancer is a heterogeneous disease driven by genetic mutations and epigenetic changes. Approximately 80% of sporadic colorectal cancers are initiated by mutation and inactivation of the adenomatous polyposis coli (APC) gene, which results in unrestrained intestinal epithelial growth and formation of adenomas. Aberrant DNA methylation promotes cancer progression by the inactivation of tumor suppressor genes via promoter methylation. In addition, global DNA hypomethylation is often seen before the formation of adenomas, suggesting that it contributes to neoplastic transformation. Previous studies employed mice with a hypomorphic mutation in DNA methyltransferase 1 (Dnmt1), which exhibited constitutive global DNA hypomethylation and decreased tumorigenesis in the ApcMin/+ mouse model of intestinal cancer. However, the consequences of intestinal epithelial-specific acute hypomethylation during ApcMin/+ tumor initiation have not been reported. Using temporally controlled intestinal epithelial-specific gene ablation, we show that total loss of Dnmt1 in the ApcMin/+ mouse model of intestinal cancer causes accelerated adenoma initiation. Deletion of Dnmt1 precipitates an acute response characterized by hypomethylation of repetitive elements and genomic instability, which surprisingly is followed by remethylation with time. Two months post-Dnmt1 ablation, mice display increased macroadenoma load, consistent with a role for Dnmt1 and DNA methylation in maintaining genomic stability. These data suggest that DNA hypomethylation plays a previously unappreciated role in intestinal adenoma initiation. Cancer Prev Res; 9(7); 534–46. ©2016 AACR.See related article by Lee and Laird, p. 509