Methodical: Redefining Promoters Based on Transcriptional Regulation By DNA Methylation

Author(s): Richard Heery

Affiliation(s): European Institute of Oncology



DNA methylation at gene promoters is generally considered to be associated with transcriptional repression. However, lack of a clear picture of where promoter methylation is most important has obscured our understanding of this relationship and resulted in a wide variety of arbitrary promoter definitions being used in different DNA methylation studies. These vary substantially in both their length and location relative to the transcription start site (TSS) and lead to inconsistency between promoter methylation studies. We are developing Methodical, a computational method and associated package that combines RNA-seq and WGBS data to identify genomic regions where DNA methylation tends to be highly correlated with nearby TSS activity. We refer to these regions as TSS-proximal methylation-controlled regulatory sites (TMRs). We applied Methodical to one normal prostate tissue data set, one prostate tumour dataset and one prostate metastases dataset and characterized the identified TMRs. We reveal that, in contrast with the conventional idea that DNA methylation silences transcription, a substantial minority of TMRs display positive methylation-transcription correlations. We also show that the region just downstream of the TSS is the most common location for TMRs and that negative and positive TMRs are enriched for different genomic features and chromatin states. Finally, we demonstrate that TMRs have a tendency to become highly hypermethylated in diverse cancer types.