Significance In mammals, when and where a gene is transcribed are primarily regulated by the activity of regulatory DNA elements, or enhancers. Genetic mutation disrupting enhancer function is emerging as one of the major causes of human diseases. However, our knowledge remains limited about the location and activity of enhancers in the numerous and distinct cell types and tissues. Here, we develop a computational approach, regulatory element prediction based on tissue-specific local epigenetic marks (REPTILE), to precisely locate enhancers based on genome-wide DNA methylation and histone modification profiling. We systematically tested REPTILE on a variety of human and mouse cell types and tissues. Compared with existing methods, we found that enhancer predictions from REPTILE are more likely to be active in vivo and the predicted locations are more accurate.

Abstract Accurate enhancer identification is critical for understanding the spatiotemporal transcriptional regulation during development as well as the functional impact of disease-related noncoding genetic variants. Computational methods have been developed to predict the genomic locations of active enhancers based on histone modifications, but the accuracy and resolution of these methods remain limited. Here, we present an algorithm, regulatory element prediction based on tissue-specific local epigenetic marks (REPTILE), which integrates histone modification and whole-genome cytosine DNA methylation profiles to identify the precise location of enhancers. We tested the ability of REPTILE to identify enhancers previously validated in reporter assays. Compared with existing methods, REPTILE shows consistently superior performance across diverse cell and tissue types, and the enhancer locations are significantly more refined. We show that, by incorporating base-resolution methylation data, REPTILE greatly improves upon current methods for annotation of enhancers across a variety of cell and tissue types. REPTILE is available at https://github.com/yupenghe/REPTILE/.

Footnotes Author contributions: Y.H. designed research; Y.H., D.U.G., D.E.D., J.R.N., R.G.C., A.Y.L., Y.S., A.V., L.A.P., and B.R. performed research; D.E.D., A.V., and L.A.P. collected the tissues from E11.5 mouse embryo, which were later profiled for epigenetic marks; D.U.G., A.Y.L., Y.S., and B.R. generated the histone modification data for the E11.5 tissues; D.E.D., A.V., and L.A.P. conducted transgenic mouse assay and generated the newly validated VISTA enhancers; J.R.N. and R.G.C. generated the whole-genome bisulfite sequencing data for the E11.5 tissues; Y.H. analyzed data; Y.H., D.U.G., B.R., and J.R.E. wrote the paper; and J.R.E. supervised the project.

Reviewers: P.A.J., Van Andel Institute; and U.O., Max Delbrueck Center for Molecular Medicine.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1618353114/-/DCSupplemental.