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Title: An integrated epigenetic and genetic analysis of DNA methyltransferase genes (DNMTs) in tumor resistant and susceptible chicken lines

item YU, YING
item Zhang, Huanmin
item TIAN, FEI

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/12/2008
Publication Date: 7/16/2008
Citation: Yu, Y., Zhang, H., Tian, F., Zhang, W., Fang, H., Song, J. 2008. An Integrated Epigenetic and Genetic Analysis of DNA Methyltransferase Genes (DNMTs) in Tumor Resistant and Susceptible Chicken Lines. PLoS One. 3(7):1-13.

Interpretive Summary: Similar to cancer in human, researchers have been trying hard to understand genetic control of Marek’s disease resistance and susceptibility, yet much still is unknown and Marek’s disease continues to pose a serious threat to poultry industry. This study investigated the role of a group of important enzymes known as DNA methyltransferases, which are involved with important gene expression processes, in lines of chickens either resistant or susceptible to Marek’s disease. The findings of this study may help advance the scientific understanding and formulate new strategies to augment the current vaccinal control of the disease.

Technical 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 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.