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. 2015 May 27:5:24.
doi: 10.1186/s13578-015-0013-2. eCollection 2015.

Association of aberrant DNA methylation in Apc(min/+) mice with the epithelial-mesenchymal transition and Wnt/β-catenin pathways: genome-wide analysis using MeDIP-seq

Yue Guo #  1   2 , Jong Hun Lee #  3 , Limin Shu  2 , Ying Huang  1   2 , Wenji Li  2 , Chengyue Zhang  1   2 , Anne Yuqing Yang  1   2 , Sarandeep Ss Boyanapalli  1   2 , Ansu Perekatt  4 , Ronald P Hart  5 , Michael Verzi  4 , Ah-Ng Tony Kong  2
Affiliations

Association of aberrant DNA methylation in Apc(min/+) mice with the epithelial-mesenchymal transition and Wnt/β-catenin pathways: genome-wide analysis using MeDIP-seq

Yue Guo et al. Cell Biosci. .

Abstract

Background: Aberrant DNA methylation at the 5-carbon on cytosine residues (5mC) in CpG dinucleotides is probably the most extensively characterized epigenetic modification in colon cancer. It has been suggested that the loss of adenomatous polyposis coli (APC) function initiates tumorigenesis and that additional genetic and epigenetic events are involved in colon cancer progression. We aimed to study the genome-wide DNA methylation profiles of intestinal tumorigenesis in Apc(min/+) mice.

Results: Methylated DNA immunoprecipitation (MeDIP) followed by next-generation sequencing was used to determine the global profile of DNA methylation changes in Apc(min/+) mice. DNA was extracted from adenomatous polyps from Apc(min/+) mice and from normal intestinal tissue from age-matched Apc(+/+) littermates, and the MeDIP-seq assay was performed. Ingenuity Pathway Analysis (IPA) software was used to analyze the data for gene interactions. A total of 17,265 differentially methylated regions (DMRs) displayed a ≥ 2-fold change (log2) in methylation in Apc(min/+) mice; among these DMRs, 9,078 (52.6 %) and 8,187 (47.4 %) exhibited increased and decreased methylation, respectively. Genes with altered methylation patterns were mainly mapped to networks and biological functions associated with cancer and gastrointestinal diseases. Among these networks, several canonical pathways, such as the epithelial-mesenchymal transition (EMT) and Wnt/β-catenin pathways, were significantly associated with genome-wide methylation changes in polyps from Apc(min/+) mice. The identification of certain differentially methylated molecules in the EMT and Wnt/β-catenin pathways, such as APC2 (adenomatosis polyposis coli 2), SFRP2 (secreted frizzled-related protein 2), and DKK3 (dickkopf-related protein 3), was consistent with previous publications.

Conclusions: Our findings indicated that Apc(min/+) mice exhibited extensive aberrant DNA methylation that affected certain signaling pathways, such as the EMT and Wnt/β-catenin pathways. The genome-wide DNA methylation profile of Apc(min/+) mice is informative for future studies investigating epigenetic gene regulation in colon tumorigenesis and the prevention of colon cancer.

Keywords: DNA methylation; Epigenetic; Epithelial-mesenchymal transition pathway; MeDIP-seq; Wnt/β-catenin pathway.

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Figures

Fig. 1
Fig. 1
Global changes in the DNA methylation profile between Apc mutant adenomatous polyps and control tissue. a, Total number of peaks generated by MeDIP-seq. b, Number of DMRs with significantly increased or decreased changes in methylation (≥2-fold in log2) in polyps from Apcmin/+ mice
Fig. 2
Fig. 2
The 5 most significant biological functions and diseases related to changes in the methylation patterns. The number of molecules in the dataset associated with a known function was determined by IPA functional analysis
Fig. 3
Fig. 3
The most significant networks determined by IPA: cancer, cell cycle, and molecular transport. The IPA network analysis was conducted using the genes that were differentially methylated and their close relationships. IPA used triangle connectivity based on 30 focus genes and built the network according to the number of interactions between a single gene and others in the existing network. Red, increased methylation; green, decreased methylation
Fig. 4
Fig. 4
The 15 most significant canonical pathways related to changes in the methylation patterns. The left y-axis (bar graph) presents the data as the log (p-value) of each pathway using Fisher’s exact test. The right y-axis (line graph) corresponds to the ratio data for each pathway. The ratios were calculated as the number of input molecules mapped to a specific pathway divided by the total number of molecules in the given pathway
Fig. 5
Fig. 5
Predicted interactions between molecules with altered methylation that mapped to the EMT and Wnt/β-catenin pathways. IPA predicted direct interaction of the genes with altered methylation patterns in the EMT and Wnt/β-catenin pathways based on the publication database. Red, increased methylation; green, decreased methylation
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