title: Frequent hypermethylation of orphan CpG islands with enhancer activity in cancer.
abstract: CpG islands (CGIs) are interspersed DNA sequences that have unusually high CpG ratios and GC contents. CGIs are typically located in the promoter of protein-coding genes. They normally lack DNA methylation but become hypermethylated and induce repression of associated genes in cancer. However, the biological functions of non-promoter CGIs (orphan CGIs) largely remain unclear.
  
  
  
  Here, we identify orphan CGIs that do not map to the promoter of any protein-coding or non-coding transcripts but possess chromatin and transcriptional marks that reflect enhancer activity (termed eCGIs). They exhibit three-dimensional chromatin looping toward multiple target genes with high affinity. Intriguingly, transcription regulators were frequently associated with such CGI-containing enhancers. Remarkably, our analyses in cell lines and clinical tissues showed that eCGIs have more dynamic DNA methylation changes in cancer relative to promoter CGIs. The observed eCGI hypermethylation was accompanied by a loss of enhancer marks and transcriptional inactivation of the target genes.
  
  
  
  Our results suggest that eCGIs may constitute a distinct class of enhancers and perform a more instrumental role in tumorigenesis than typical CGIs in gene promoters.
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon, 305-701, Republic of Korea.
authors.forename: Min Gyun
authors.initials: MG
authors.lastname: Bae
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon, 305-701, Republic of Korea.
authors.forename: Jeong Yeon
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Bio and Brain Engineering, KAIST, Daejeon, 305-701, Republic of Korea. jungkyoon@kaist.ac.kr.
authors.forename: Jung Kyoon
authors.initials: JK
authors.lastname: Choi
mesh_terms: D045744:Cell Line, Tumor; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D057890:Epigenomics; D020869:Gene Expression Profiling; D006801:Humans; D014158:Transcription, Genetic / Q000235:genetics
keywords: Cancer; CpG islands; DNA methylation; Enhancers