Abstract
BackgroundAberrant 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 Apcmin/+ mice.ResultsMethylated DNA immunoprecipitation (MeDIP) followed by next-generation sequencing was used to determine the global profile of DNA methylation changes in Apcmin/+ mice. DNA was extracted from adenomatous polyps from Apcmin/+ 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 Apcmin/+ 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 Apcmin/+ 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.ConclusionsOur findings indicated that Apcmin/+ 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 Apcmin/+ mice is informative for future studies investigating epigenetic gene regulation in colon tumorigenesis and the prevention of colon cancer.
Highlights
It is widely accepted that the accumulation of genetic and epigenetic alterations contributes to cancer initiation and progression
Genetic alterations refer to mutations in tumor suppressor genes and oncogenes, whereas epigenetic modifications involve changes in chromatin structure that result in altered gene expression without primary changes to the DNA sequence [1]
We examined the global DNA methylation profile in the well-established Apcmin/+ intestinal tumorigenesis mouse model using methylated DNA immunoprecipitation (MeDIP) and next-generation sequencing (MeDIP-seq)
Summary
It is widely accepted that the accumulation of genetic and epigenetic alterations contributes to cancer initiation and progression. Aberrant DNA methylation at the 5-carbon on cytosine residues (5mC) in CpG dinucleotides is perhaps the most extensively characterized epigenetic modification in cancer. DNA methylation affects the rate of gene transcription and regulates various biological processes, such as proliferation, apoptosis, DNA repair, cancer initiation, and cancer progression [3]. Global genome-wide loss of methylation has been associated with increased genomic instability and proto-oncogene activation, whereas DNA hypermethylation of CpG islands in promoter regions silences tumor suppressor genes [6]. 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 Apcmin/+ mice
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