Expression of eukaryotic genes with complex spatial-temporal regulation during development requires finer regulation than that of genes with simpler expression patterns. Given the high degree of conservation of the developmental gene set across distantly related phylogenetic taxa, it is argued that evolutionary variation has occurred by tweaking regulation of expression of developmental genes, rather than by changes in genes themselves. Complex regulation is often achieved through the coordinated action of transcription regulatory elements spread across the genome up to tens of kilobases from the promoters of their target genes. Disruption of regulatory elements has been implicated in several diseases and studies showing associations between disease traits and nonprotein coding variation hint for a role of regulatory elements as cause of diseases. Therefore, the identification and mapping of regulatory elements in genome scale is crucial to understand how gene expression is regulated, how organisms evolve, and to identify sequence variation causing diseases. Previously developed experimental techniques have been adapted to identify regulatory elements in genome scale and high-throughput, allowing a global view of their biological roles. We review methods as chromatin immunoprecipitation, DNase I hypersensitivity, and computational approaches and how they have been employed to generate maps of histone modifications, open chromatin, nucleosome positioning, and transcription factor binding regions in whole mammalian genomes. Given the importance of non-promoter elements in gene regulation and the recent explosion in the number of studies devoted to them, we focus on these elements and discuss the insights on gene regulation being obtained by these studies.
