5 research outputs found
Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer
Background: One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions
contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized.
Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at
other loci are not well characterized.
Results: Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a
type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as
super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with
the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally
active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability
within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors
contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles
with impact on transforming processes during carcinogenesis.
Conclusions: We develop an extensive catalogue of human DNA methylomes at base resolution to better
understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG
methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by
specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes.peerReviewe