title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 USA.|Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, Piscataway, NJ 08854 USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Food Science and Biotechnology, College of Life Science, CHA University, Gyeonggi-do, 463-400 South Korea.
authors.forename: Jong Hun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, Piscataway, NJ 08854 USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Shu
authors.affiliation: Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 USA.|Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, Piscataway, NJ 08854 USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, Piscataway, NJ 08854 USA.
authors.forename: Wenji
authors.initials: W
authors.lastname: Li
authors.affiliation: Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 USA.|Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, Piscataway, NJ 08854 USA.
authors.forename: Chengyue
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 USA.|Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, Piscataway, NJ 08854 USA.
authors.forename: Anne Yuqing
authors.initials: AY
authors.lastname: Yang
authors.affiliation: Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 USA.|Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, Piscataway, NJ 08854 USA.
authors.forename: Sarandeep Ss
authors.initials: SS
authors.lastname: Boyanapalli
authors.affiliation: Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 USA.
authors.forename: Ansu
authors.initials: A
authors.lastname: Perekatt
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 USA.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Hart
authors.affiliation: Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Verzi
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Room 228, 160 Frelinghuysen Road, Piscataway, NJ 08854 USA.
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
keywords: DNA methylation; Epigenetic; Epithelial-mesenchymal transition pathway; MeDIP-seq; Wnt/β-catenin pathway