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REVIEWS
R E G U L ATO RY E L E M E N T S
Transcriptional enhancers: from properties to genome-wide predictions
Daria Shlyueva*, Gerald Stampfel* and Alexander Stark
Abstract | Cellular development, morphology and function are governed by precise patterns of gene expression. These are established by the coordinated action of genomic regulatory elements known as enhancers or cis-regulatory modules. More than 30years after the initial discovery of enhancers, many of their properties have been elucidated; however, despite major efforts, we only have an incomplete picture of enhancers in animal genomes. In this Review, we discuss how properties of enhancer sequences and chromatin are used to predict enhancers in genome-wide studies. We also cover recently developed high-throughput methods that allow the direct testing and identification of enhancers on the basis of their activity. Finally, we discuss recent technological advances and current challenges in the field of regulatory genomics.
During animal development, a single cell the fertilized egg gives rise to a multitude of different cell types and organs. These acquire different morphologies and functions by expressing different sets of genes. The initial step in gene expression is the transcription of the genomic DNA of the gene into RNA by RNA polymeraseII (PolII). The genomic sequence in the immediate vicinity of the transcription start site (TSS), which is also known as the core promoter, is sufficient to assemble the PolII machinery. However, transcription is often weak in the absence of regulatory DNA regions that are more distant from the TSS; these regions are called enhancers or cis-regulatory modules (CRMs).
More than 30years ago, the first enhancer was identified as a 72-bp sequence of the SV40 virus genome, which could enhance the transcription of a reporter gene in HeLa cells by several hundred fold1. Soon after this, cellular enhancers were found in animal genomes2;
since then, many enhancers have been described, and their biochemical and functional properties have been extensively studied (FIG.1).
Enhancer sequences contain short DNA motifs that act as binding sites for sequence-specific transcription factors (FIG.1a). These proteins recruit co-activators and co-repressors such that the combined regulatory cues of all bound factors determine the activity of the enhancer. In addition, enhancer activity has been shown to correlate with certain properties of chromatin
(FIG.2):...