Genome-wide analysis of DNA methylation in UVB- and DMBA/TPA-induced mouse skin cancer models

Abstract

Aims Ultraviolet irradiation and carcinogens have been reported to induce epigenetic alterations, which potentially contribute to the development of skin cancer. We aimed to study the genome-wide DNA methylation profiles of skin cancers induced by ultraviolet B (UVB) irradiation and 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-1,3-acetate (TPA). Main methods Methylated DNA immunoprecipitation (MeDIP) followed by next-generation sequencing was utilized to ascertain the DNA methylation profiles in the following common mouse skin cancer models: SKH-1 mice treated with UVB irradiation and CD-1 mice treated with DMBA/TPA. Ingenuity® pathway analysis (IPA) software was utilized to analyze the data and to identify gene interactions among the different pathways. Key findings 6,003 genes in the UVB group and 5,424 genes in the DMBA/TPA group exhibited a greater than 2-fold change in CpG methylation as mapped by the IPA software. The top canonical pathways identified by IPA after the two treatments were ranked were pathways related to cancer development, cAMP-mediated signaling, G protein-coupled receptor signaling and PTEN signaling associated with UVB treatment, whereas protein kinase A signaling and xenobiotic metabolism signaling were associated with DMBA/TPA treatment. In addition, the mapped IL-6-related inflammatory pathways displayed alterations in the methylation profiles of inflammation-related genes linked to UVB treatment. Significance Genes with altered methylation were ranked in the UVB and DMBA/TPA models, and the molecular interaction networks of those genes were identified by the IPA software. The genome-wide DNA methylation profiles of skin cancers induced by UV irradiation or by DMBA/TPA will be useful for future studies on epigenetic gene regulation in skin carcinogenesis.

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

“…MeDIP was performed using a MagMedIP kit (Diagenode, Denville, NJ, USA) as previously described [ 63 ]. Briefly, immunoprecipitations were performed using a monoclonal antibody against 5-methylcytidine (Diagenode, Denville, NJ, USA) to separate the methylated DNA fragments from the unmethylated fragments.…”

“…Subsequently, the samples were subjected to Illumina next-generation sequencing (Otogenetics Corporation, Norcross, GA, USA). After downloading the BAM files for analysis, MeDIP alignments were compared with control samples using Cuffdiff 2.0.2 as previously described [ 64 , 63 ]. To judge the quantitative enrichment in MeDIP samples versus control samples in Cuffdiff, the overlapping regions of sequence alignment common to the MeDIP and control samples were used.…”

Fucoxanthin Elicits Epigenetic Modifications, Nrf2 Activation and Blocking Transformation in Mouse Skin JB6 P+ Cells

“…For example, drugs that target histone deacetylases (HDACs) and DNA methyltransferase (DNMT) inhibitors have been approved by the FDA as chemotherapeutics, although their toxicity limits their applications (12, 13). Aberrant epigenetic alterations have been observed in the initiation and progression of skin cancers (14–17). Certain dietary phytochemicals that possess chemopreventive effects have been reported to prevent cancer by targeting epigenetic modifications (18, 19).…”

Epigenetic blockade of neoplastic transformation by bromodomain and extra-terminal (BET) domain protein inhibitor JQ-1

“…DNA methylation on 5-cytosine (5-mC) and covalent modifications to histone tails are the major mechanisms that maintain DNA stability and control gene transcription at the epigenetic level. Recent publications from our group and others have identified that aberrant DNA methylation is associated with altered gene expression in cancer models in vitro and in vivo [1, 2]. In addition, loss of 5-hydroxymethylcytosine (5-hmC) and ten-eleven translocation 2 (TET2) protein expression has been reported in malignant melanoma [3].…”