DMRscaler: A Scale-Aware Method to Identify Regions of Differential DNA Methylation Spanning Basepair to Multi-Megabase Features

Pathogenic mutations in genes that regulate chromatin structure and function cause epigenetic aberrations that result in rare genetic syndromes. These chromatin modifiers exhibit extraordinary diversity in the scale of the epigenetic changes they affect, from single basepair modifications by DNMT1 to whole genome structural changes by PRM1/2. Patterns of DNA methylation are related to a diverse set of epigenetic features across this full range of epigenetic scale, making DNA methylation valuable for mapping regions of general epigenetic dysregulation. However, no existing methods make use of these relations to accurately identify the scale of epigenetic changes directly from DNA methylation data. To address this, we developed DMRscaler, a novel method that uses an iterative windowing procedure to capture regions of differential DNA methylation (DMRs) ranging in size from single basepairs to whole chromosomes. We benchmarked DMRscaler against several methylation callers in both simulated and natural data comparing XX and XY peripheral blood samples. DMRscaler was the only method that accurately called DMRs ranging in size from 100 bp to 1 Mb (pearsons r = 0.92) and up to 152Mb on the X-chromosome. We then analyzed methylation data from rare-disease cohorts that harbor mutations in the chromatin modifier genes NSD1, EZH2, and KAT6A. DMRscaler identified full or partial novel DMRs spanning PCDHA, PCDHB and PCDHG gene clusters across these three groups suggesting these are common mechanisms driving their dysregulation in early development. Taken together, our results show DMRscaler is uniquely able to capture the scale of DMR features and identify novel, co-regulated regions that drive epigenetic dysregulation in human disease.