DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes.

Genome Biol 2013 Mar 12;14(3):R21. Epub 2013 Mar 12.

Background: Abnormal epigenetic marking is well documented in gene promoters of cancer cells, but the study of distal regulatory siteshas lagged behind.We performed a systematic analysis of DNA methylation sites connected with gene expression profilesacross 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 downregulation. Moreover, the association between enhancer methylation and gene deregulation in cancerwas significantly stronger than the association of promoter methylationwith 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 constantlyopen 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.

Download full-text PDF

Source
http://dx.doi.org/10.1186/gb-2013-14-3-r21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053839PMC
March 2013
15 Reads

Publication Analysis

Top Keywords

enhancer sites
12
distal regulatory
12
gene expression
12
dna methylation
12
sites
10
sites closely
8
dysregulation cancer
8
gene promoters
8
gene
8
closely gene
8
methylation gene
8
regulatory sites
8
expression levels
8
cell types
8
methylation distal
8
methylation
7
expression
6
enhancer
5
distal genes
4
levels cell
4

Altmetric Statistics

References

(Supplied by CrossRef)

Similar Publications