Gene activation by metazoan enhancers: Diverse mechanisms stimulate distinct steps of transcription

Enhancers can stimulate transcription by a number of different mechanisms which control different stages of the transcription cycle of their target genes, from recruitment of the transcription machinery to elongation by RNA polymerase. These mechanisms may not be mutually exclusive, as a single enhancer may act through different pathways by binding multiple transcription factors. Multiple enhancers may also work together to regulate transcription of a shared target gene. Most of the evidence supporting different enhancer mechanisms comes from the study of single genes, but new high-throughput experimental frameworks offer the opportunity to integrate and generalize disparate mechanisms identified at single genes. This effort is especially important if we are to fully understand how sequence variation within enhancers contributes to human disease.

Enhancers are regulatory elements that bind transcription factors and activate expression of their target genes by stimulating specific steps in the RNA polymerase II transcription cycle. Here we review the mechanisms of enhancer action and highlight opportunities for new insights from high-throughput experimental technologies such as massively parallel reporter assays.

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