REDEFINING PROMOTER DNA METHYLATION CHANGE IN CANCER

Promoter DNA methylation has been recognized for decades as one of the major mechanisms of epigenetic gene regulation and has consistently been found to be perturbed during cancer development. However, among the many genomic regions that have been found to display altered methylation in different cancer types, exactly which changes play a causative role in cancer development and how they impact the cancer transcriptome remains poorly understood. We developed two computational tools, MethylDriver and Methodical, to advance our understanding of the relationship between DNA methylation and transcription and how this relationship is perturbed in cancer and to identify methylation changes that are most likely playing a causative role in cancer development. MethylDriver leverages epigenetic covariates to separate promoter methylation changes which may be under selection and playing a causative role during tumour progression from the many changes which are likely incidental to cancer development. We applied MethylDriver to 13 different cancer types from The Cancer Genome atlas (TCGA) to identify putative epigenetic drivers in a variety of cancer types, uncovering relatively small sets of differentially methylated promoters with increased relevance to cancer biology. Despite these findings, we were surprised by the generally poor correlations we observed between promoter DNA methylation and transcriptional expression of their associated genes and also by the lack of consensus for the general extent of promoter regions around transcriptional start sites (TSS). We thus developed Methodical, a computational method 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 8 chromatin states. Finally, we demonstrate that TMRs are among the regions most affected by DNA methylation change in diverse cancer types.