Genome-wide quantification of the effects of DNA methylation on human gene regulation

Changes in DNA methylation affect development and disease, but not all regulatory elements act in a methylation-dependent (MD) manner. Here, we developed mSTARR-seq, a high-throughput approach that we used to quantify genome-wide MD regulatory activity across three human cell types. We identify thousands of MD regulatory elements, show that MD activity is predictable using sequence and chromatin state information, and identify specific transcription factors associated with higher activity in unmethylated or methylated states. MD regulatory elements exhibit greater cell type specificity than MD-independent elements, and explain variation in the strength of DNA methylation-gene expression correlations in vivo. Our findings thus provide a multi-tissue map of MD regulatory activity in the human genome, facilitating functional interpretation of the many emerging associations between methylation and trait variation.