title: Retrotransposon-specific DNA hypomethylation and two-step loss-of-imprinting during WW45 haploinsufficiency-induced hepatocarcinogenesis.
abstract: Liver cancer development follows a multistep process that includes epigenetic changes beginning at the initiation stage, changes that have been studied for their potential diagnostic value. Here, we examined long-term, cancer-associated epigenetic changes during carcinogenesis using a mouse model of liver cancer. WW45-haploinsufficient (WW45(+/-)) mice developed liver cancer after 12 months due to dysregulation of the Hippo pathway and consequent Yap overexpression. There was no pathological sign of neoplastic regions in the livers of 10-month-old WW45(+/-) mice but whole-gene expression patterns statistically proved the resemblance between 10-month-old livers and hepatomas from WW45(+/-) mice. We found epigenetic features in the livers of 10-month-old WW45(+/-) mice which were already distinctive from the wild-type counterparts prior to tumorigenesises. H19 ICR showed loss-of-imprinting in two steps and allelic histone marker signature during tumorigenesis showed similarity with ES cells. Progressive cancer pathognomonic global hypomethylation was a characteristic post-10-month feature and was well reflected in retrotransposons. Heterochromatic histone modifications also decreased in retrotransposons after 10 months in the liver of WW45(+/-) mice. This study showed potential epigenetic features for cancer prognostic use and supported the epigenetic progenitor model of cancer.
authors.affiliation: National Creative Research Initiatives Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, South Korea.
authors.forename: Ji Yun
authors.initials: JY
authors.lastname: Song
authors.forename: Joo-Hyeon
authors.initials: JH
authors.lastname: Lee
authors.forename: Cheol O
authors.initials: CO
authors.lastname: Joe
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Chung
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019175:DNA Methylation; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018392:Genomic Imprinting; D057895:Haploinsufficiency; D006657:Histones / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D018626:Retroelements
chemical_list: D018797:Cell Cycle Proteins; D006657:Histones; C513121:IGF2 protein, mouse; D018626:Retroelements; C485935:Sav1 protein, mouse; D007335:Insulin-Like Growth Factor II