Abstract
Both epigenetic alterations and genetic variations play essential roles in tumorigenesis. The epigenetic modification of DNA methylation is catalyzed and maintained by the DNA methyltransferases (DNMT3a, DNMT3b and DNMT1). DNA mutations and DNA methylation profiles of DNMTs themselves and their relationships with chicken neoplastic disease resistance and susceptibility are not yet defined. In the present study, we analyzed the complexity of the DNA methylation variations and DNA mutations in the first exon of three DNMTs genes over generations, tissues, and ages among chickens of two highly inbred White Leghorn lines, Marek's disease-resistant line 63 and -susceptible line 72, and six recombinant congenic strains (RCSs). Among them, tissue-specific methylation patterns of DNMT3a were disclosed in spleen, liver, and hypothalamus in lines 63 and 72. The methylation level of DNMT3b on four CpG sites was not significantly different among four tissues of the two lines. However, two line-specific DNA transition mutations, CpG→TpG (Chr20:10203733 and 10203778), were discovered in line 72 compared to the line 63 and RCSs. The methylation contents of DNMT1 in blood cell showed significant epimutations in the first CpG site among the two inbred lines and the six RCSs (P<0.05). Age-specific methylation of DNMT1 was detected in comparisons between 15 month-old and 2 month-old chickens in both lines except in spleen samples from line 72. No DNA mutations were discovered on the studied regions of DNMT1 and DNMT3a among the two lines and the six RCSs. Moreover, we developed a novel method that can effectively test the significance of DNA methylation patterns consisting of continuous CpG sites. Taken together, these results highlight the potential of epigenetic alterations in DNMT1 and DNMT3a, as well as the DNA mutations in DNMT3b, as epigenetic and genetic factors to neoplastic diseases of chickens.
Highlights
The relationship between somatic epigenetic variations and genetic mutations of germlines has been an emerging area in exploring tumorigenesis [1,2]
Our results indicated that DNMT1 had a similar methylation pattern in the spleen, liver, and hypothalamus (Figure 8A, 8B and 8C) between the two inbred lines at 15 months of age, whereas the CpG site 1 in blood cell showed a significant epimutation among the two parental lines and the six recombinant congenic strains (RCSs) (P,0.05) (Figure 8D) at 12 months of age
To explore which CpG site in a continuous CpG sites region (CpG islands) is mainly responsible for the fluctuation of the methylation level and classification of methylation patterns, we developed a new method to quantitatively evaluate the methylation patterns of DNA Methyltransferase Genes (DNMTs) via a nonparametric analysis method that transforms principle component analysis (PCA) as an exact F test
Summary
The relationship between somatic epigenetic variations and genetic mutations of germlines has been an emerging area in exploring tumorigenesis [1,2]. Epigenetic and genetic mechanisms all contribute to the development of cancers [3,4,5,6]. Single nucleotide polymorphisms (SNPs) are quite common genetic mutations in general populations, and one third of SNPs in humans have been associated with increased or decreased risks of various diseases, including cancers [7,8,9,10,11,12]. Epigenetics, first described by Conrad Waddington six decades ago, is defined as the heritable changes in gene expression that occur without an alteration in DNA sequence [13]. Aberrant DNA methylation, one of the epigenetic modifications, is mitotically heritable. The genomes of cancer cells are often hypomethylated in repetitive elements and hypermethylated in the promoter and/ or the first exon region of tumor suppressor genes compared to their normal counter-parts [14,15]
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