Comprehensive profiling of zebrafish hepatic proximal promoter CpG island methylation and its modification during chemical carcinogenesis

Abstract

BackgroundDNA methylation is an epigenetic mechanism associated with regulation of gene expression and it is modulated during chemical carcinogenesis. The zebrafish is increasingly employed as a human disease model; however there is a lack of information on DNA methylation in zebrafish and during fish tumorigenesis.ResultsA novel CpG island tiling array containing 44,000 probes, in combination with immunoprecipitation of methylated DNA, was used to achieve the first comprehensive methylation profiling of normal adult zebrafish liver. DNA methylation alterations were detected in zebrafish liver tumors induced by the environmental carcinogen 7, 12-dimethylbenz(a)anthracene. Genes significantly hypomethylated in tumors were associated particularly with proliferation, glycolysis, transcription, cell cycle, apoptosis, growth and metastasis. Hypermethylated genes included those associated with anti-angiogenesis and cellular adhesion. Of 49 genes that were altered in expression within tumors, and which also had appropriate CpG islands and were co-represented on the tiling array, approximately 45% showed significant changes in both gene expression and methylation.ConclusionThe functional pathways containing differentially methylated genes in zebrafish hepatocellular carcinoma have also been reported to be aberrantly methylated during tumorigenesis in humans. These findings increase the confidence in the use of zebrafish as a model for human cancer in addition to providing the first comprehensive mapping of DNA methylation in the normal adult zebrafish liver.

Alkaline phosphatase gene sequence characteristics and transcriptional regulation by phosphate limitation in Karenia brevis (Dinophyceae)

“…For dinoflagellates, only Amphidinium carterae has been the subject of dedicated AP gene study, in which a full-length AP cDNA sequence was isolated and the gene expression pattern induced by DIP limitation was investigated (Lin et al, 2011). A recent microarray study on the toxic dinoflagellate Karenia brevis Davis under N, P-stress revealed an AP-like transcript (Morey et al, 2011) but its sequence is not yet publically available.…”

Oxidative stress and hypermethylation induced by exposure of Oreochromis niloticus to complex environmental mixtures of river water from Cubatão do Sul, Brazil

“…Several studies report the rates for different types of waste and substances, such as pesticides, and for various tissues and organs such as kidneys, liver and gills (Aniagu et al, 2008;Contractor et al, 2004;Jin et al, 2010;Mirbahai et al, 2011;Shugart, 1990;Strömqvist et al, 2010;Velisek et al, 2011;Wang et al, 2009;Xing et al, 2012;Zhou et al, 2001).…”

Liver development and cancer formation in zebrafish

“…In zebrafish HCC, several IGF-binding proteins (IGFBPs), such as igfbp2b, were significantly hypomethylated and may have upregulated the expression of IGF-2 (Mirbahai et al, 2011). In the early stages of tumorigenesis in highly proliferating tumor cells, the lack of a vascular supply results in hypoxia (Kelly et al, 2008;Mirbahai et al, 2011). The anaerobic conditions and the presence of IGF result in increased expression of hypoxiainducible factor 1 (HIF-1) (Kelly et al, 2008).…”

“…Following liver damage or viral transactivation, the IGF-2 receptor is upregulated by altered methylation of the IGF-2 promoter Whittaker et al, 2010). In zebrafish HCC, several IGF-binding proteins (IGFBPs), such as igfbp2b, were significantly hypomethylated and may have upregulated the expression of IGF-2 (Mirbahai et al, 2011). In the early stages of tumorigenesis in highly proliferating tumor cells, the lack of a vascular supply results in hypoxia (Kelly et al, 2008;Mirbahai et al, 2011).…”

“…The genes with altered methylation in zebrafish HCC are associated with biological functions, such as cell death, cell morphology, inflammatory response, DNA repair, and replication, and induced molecules involved in cancer formation, such as c-jun, shc, and pka (Mirbahai et al, 2010). Many HCCs exhibit methylation of at least one TSG promoter, particularly SOGS-1, APC, E-cadherin, and p15.…”