title: Decrease of 5hmC in gastric cancers is associated with TET1 silencing due to with DNA methylation and bivalent histone marks at TET1 CpG island 3'-shore.
abstract: Recent evidence has shown that the level of 5-hydroxymethylcytosine (5 hmC) in chromosomal DNA is aberrantly decreased in a variety of cancers, but whether this decrease is a cause or a consequence of tumorigenesis is unclear. Here we show that, in gastric cancers, the 5 hmC decrease correlates with a decrease in ten-eleven translocation 1 (TET1) expression, which is strongly associated with metastasis and poor survival in patients with gastric cancer. In gastric cancer cells, TET1-targeted siRNA induced a decrease in 5 hmC, whereas TET1 overexpression induced an increase in 5 hmC and reduced cell proliferation, thus correlating decreased 5 hmC with gastric carcinogenesis. We also report the epigenetic signatures responsible for regulating TET1 transcription. Methyl-CpG Binding Domain Sequencing and Reduced Representation Bisulfite Sequencing identified unique CpG methylation signatures at the CpG island 3'-shore region located 1.3 kb from the transcription start site of TET1 in gastric tumor cells but not in normal mucosa. The luciferase activity of constructs with a methylated 3'-shore sequence was greatly decreased compared with that of an unmethylated sequence in transformed gastric cancer cells. In gastric cancer cells, dense CpG methylation in the 3'-shore was strongly associated with TET1 silencing and bivalent histone marks. Thus, a decrease in 5 hmC may be a cause of gastric tumorigenesis owing to a decrease in TET1 expression through DNA methylation coupled with bivalent marks in the 3'-shore of TET1.
authors.affiliation: Epigenome Research Center, Genome Institute, KRIBB, Daejeon, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Jong-Lyul
authors.initials: JL
authors.lastname: Park
authors.affiliation: Epigenome Research Center, Genome Institute, KRIBB, Daejeon, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Epigenome Research Center, Genome Institute, KRIBB, Daejeon, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Seo
authors.affiliation: Epigenome Research Center, Genome Institute, KRIBB, Daejeon, Republic of Korea.
authors.forename: Oh-Hyung
authors.initials: OH
authors.lastname: Kwon
authors.affiliation: Epigenome Research Center, Genome Institute, KRIBB, Daejeon, Republic of Korea.
authors.forename: Byungho
authors.initials: B
authors.lastname: Lim
authors.affiliation: Epigenome Research Center, Genome Institute, KRIBB, Daejeon, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Mirang
authors.initials: M
authors.lastname: Kim
authors.affiliation: Epigenome Research Center, Genome Institute, KRIBB, Daejeon, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Kyu-Sang
authors.initials: KS
authors.lastname: Song
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
authors.affiliation: Departments of Preventive Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea.
authors.forename: Hyun Ja
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Departments of Preventive Medicine, College of Medicine, Hanyang University, Seoul, Republic of Korea.
authors.forename: Bo Youl
authors.initials: BY
authors.lastname: Choi
authors.affiliation: Epigenome Research Center, Genome Institute, KRIBB, Daejeon, Republic of Korea.|Department of Functional Genomics, Korea University of Science and Technology, Daejeon, Republic of Korea.
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Kim
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D044503:5-Methylcytosine / Q000031:analogs & derivatives; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000235:genetics*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing; D042421:Histone Code / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D020413:3' Untranslated Regions; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D006899:Mixed Function Oxygenases; C462539:TET1 protein, human
keywords: 3′-shore; 5-hydroxymethylcytosine; DNA methylation; TET1; bivalent mark; gastric cancer