We integrate information about histone marks, DNA methylation, DNA accessibility, and RNA expression to infer high-resolution maps of regulatory elements annotated jointly across a total of 127 cell and tissue types. We use these annotations to recognize epigenome differences that arise during lineage specification and cellular differentiation, to recognize modules of regulatory regions with coordinated activity across cell types, and to identify key regulators of these modules based on motif enrichments and regulator expression. In addition, we study the role of regulatory regions in human disease by relating our epigenomic annotations to genetic variants associated with common traits and disorders. These analyses demonstrate the importance and wide applicability of our data resource, and lead to important insights into epigenomics, differentiation, and disease. Specifically: Histone mark combinations show distinct levels of DNA methylation and accessibility, and predict differences in RNA expression levels that are not reflected in either accessibility or methylation.Megabase-scale regions with distinct epigenomic signatures show strong differences in activity, gene density, and nuclear lamina associations, suggesting distinct chromosomal domains.Approximately 5% of each reference epigenome shows enhancer and promoter signatures,
