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; Jong Hun Lee; Limin Shu; Ying Huang; Wenji Li; Chengyue Zhang; Anne Yuqing Yang; Sarandeep Ss Boyanapalli; Ansu Perekatt; Ronald P Hart; Michael Verzi; Ah-Ng Tony Kong

doi:10.1186/s13578-015-0013-2

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

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

Authors

Yue Guo^#^{1

2}, Jong Hun Lee^#³, Limin Shu², Ying Huang^{1

2}, Wenji Li², Chengyue Zhang^{1

2}, Anne Yuqing Yang^{1

2}, Sarandeep Ss Boyanapalli^{1

2}, Ansu Perekatt⁴, Ronald P Hart⁵, Michael Verzi⁴, Ah-Ng Tony Kong²

Affiliations

¹ Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 USA.
² Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, Piscataway, NJ 08854 USA.
³ Department of Food Science and Biotechnology, College of Life Science, CHA University, Gyeonggi-do, 463-400 South Korea.
⁴ Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 USA.
⁵ Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 USA.

^# Contributed equally.

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.

Grants and funding

R01 AT007065/AT/NCCIH NIH HHS/United States