Wednesday, March 13, 2013

Fwd: DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes

Fwd: please follow footer link

DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes: "Background:
Abnormal epigenetic marking is well documented in gene promoters of cancer cells, but the study of distal regulatory sites has lagged behind. We performed a systematic analysis of DNA methylation sites connected with gene expression profiles across normal and cancerous human genomes.
Results:
Utilizing methylation and expression data in 58 cell types, we developed a model for methylation-expression relationships in gene promoters and extrapolated it to the genome. We mapped numerous sites at which DNA methylation was associated with expression of distal genes. These sites bind transcription factors in a methylation-dependent manner, and carry the chromatin marks of a particular class of transcriptional enhancers. In contrast to the traditional model of one enhancer site per cell type, we found that single enhancer sites may define gradients of expression levels across many different cell types. Strikingly, the identified sites were drastically altered in cancers: hypomethylated enhancer sites associated with upregulation of cancer-related genes and hypermethylated sites with down-regulation. Moreover, the association between enhancer methylation and gene deregulation in cancer was significantly stronger than the association of promoter methylation with gene deregulation.
Conclusions:
Methylation of distal regulatory sites is closely related to gene expression levels across the genome. Single enhancers may modulate ranges of cell-specific transcription levels, from constantly-open promoters. In contrast to the remote relationships between promoter methylation and gene dysregulation in cancer, altered methylation of enhancer sites is closely related to gene expression profiles of transformed cells."

(Via Genome Biology - Latest Articles.)