title: Comparative DNA methylome analysis of endometrial carcinoma reveals complex and distinct deregulation of cancer promoters and enhancers.
abstract: BACKGROUND
  Aberrant DNA methylation is a hallmark of many cancers. Classically there are two types of endometrial cancer, endometrioid adenocarcinoma (EAC), or Type I, and uterine papillary serous carcinoma (UPSC), or Type II. However, the whole genome DNA methylation changes in these two classical types of endometrial cancer is still unknown.
  
  
  RESULTS
  Here we described complete genome-wide DNA methylome maps of EAC, UPSC, and normal endometrium by applying a combined strategy of methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylation-sensitive restriction enzyme digestion sequencing (MRE-seq). We discovered distinct genome-wide DNA methylation patterns in EAC and UPSC: 27,009 and 15,676 recurrent differentially methylated regions (DMRs) were identified respectively, compared with normal endometrium. Over 80% of DMRs were in intergenic and intronic regions. The majority of these DMRs were not interrogated on the commonly used Infinium 450K array platform. Large-scale demethylation of chromosome X was detected in UPSC, accompanied by decreased XIST expression. Importantly, we discovered that the majority of the DMRs harbored promoter or enhancer functions and are specifically associated with genes related to uterine development and disease. Among these, abnormal methylation of transposable elements (TEs) may provide a novel mechanism to deregulate normal endometrium-specific enhancers derived from specific TEs.
  
  
  CONCLUSIONS
  DNA methylation changes are an important signature of endometrial cancer and regulate gene expression by affecting not only proximal promoters but also distal enhancers.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: XiaoYun
authors.initials: X
authors.lastname: Xing
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Lowdon
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Nan
authors.initials: N
authors.lastname: Lin
authors.forename: Baoxue
authors.initials: B
authors.lastname: Zhang
authors.forename: Vasavi
authors.initials: V
authors.lastname: Sundaram
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Chiappinelli
authors.forename: Ian S
authors.initials: IS
authors.lastname: Hagemann
authors.forename: David G
authors.initials: DG
authors.lastname: Mutch
authors.affiliation: Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St, Louis MO 63108, USA. Paul.Goodfellow@osumc.edu.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000080924:Aldehyde Dehydrogenase 1 Family; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism; D041321:Chromosomes, Human, X; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004251:DNA Transposable Elements / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics; D050697:Retinal Dehydrogenase / Q000235:genetics; D017422:Sequence Analysis, DNA; D014594:Uterine Neoplasms / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004251:DNA Transposable Elements; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding; C077885:XIST non-coding RNA; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase; D004248:DNA (Cytosine-5-)-Methyltransferases; D000070957:MutL Protein Homolog 1