Abstract
BackgroundCpG 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.ResultsHere, 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.ConclusionOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-016-0198-1) contains supplementary material, which is available to authorized users.
Highlights
CpG islands (CGIs) are interspersed DNA sequences that have unusually high CpG ratios and GC contents
While 863 ~ 1409 CGIs were associated with non-coding transcripts and labeled as npCGIs, 619 ~ 1134 CGIs were classified as eCGIs because they did not map to any transcription start sites despite having active enhancer marks (Fig. 1b)
We identified eCGIs using various epigenomic and transcriptomic features based on H3K27ac sequencing, RNA-seq, and Cap Analysis of Gene Expression (CAGE) data
Summary
CpG islands (CGIs) are interspersed DNA sequences that have unusually high CpG ratios and GC contents. A significant portion of the genome is methylated at CpG sites, CGIs are usually unmethylated and remain transcriptionally active with active histone marks such as H3K4me as a result of the action of CxxC finger protein 1 (CFP1) [1,2,3,4]. Half of these CGIs are located in gene promoters and play an important role in development and cancer. The hypermethylation of promoter CGIs has been identified as one of the driving factors in cancer development because it represses the expression
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