Transcriptional control by enhancers: working remotely for improved performance.

Completion of the Human Genome Project almost twenty years ago produced a humbling surprise: biological complexity is driven not so much by the number of genes in a genome, but rather by increased regulatory diversity. The ability of multicellular organisms to turn genes on and off in various combinations not only drives the appearance of a cornucopia of differentiated cell types with vastly different functions, but also provides the capacity for homeostasis in a wide range of environmental conditions. Central to this increased regulatory capacity are DNA sequences that control gene activity. Among these, distal enhancer elements have captured the imagination of scientists since their initial discovery in 1983 [1–3], and their study continues to produce new mysteries. How do enhancers really work? How much of their action is driven by the mere binding of transcription factors? What are the roles of chromatin modifications and three-dimensional conformation in enhancer function? How about enhancer-derived RNAs (eRNAs)? Finding answers to these questions is not simply a basic science exercise, as genetic alterations leading to enhancer dysfunction, such as translocations, single nucleotide polymorphisms, and mutations are recognized sources of human variation, susceptibility to disease, and known drivers of cancer progression. Within this framework, in this issue of Transcription, we are glad to publish a series of reviews focused on enhancers. First, Lewis et al. get us started with a thorough and entertaining update on transcriptional control by enhancers and eRNAs[4]. Then, Cardiello et al. dive deeper into the fascinating world of eRNAs and other RNA species arising from regulatory elements identified by novel measurements of nascent RNA[5]. We then transition into the realm of chromatin, where Rahnamoun et al. report on the regulatory interplay between eRNAs, histone modifications, and epigenetic readers[6]. Next, Yao et al. provide an updated account of the role of enhancer reprogramming in tumorigenesis and cancer development[7]. Lastly, BarajasMora and Feeney discuss recent interesting results about the role of enhancers as organizers of chromatin configurations important for shaping the repertoire of immunoglobulins produced by VDJ recombination[8]. Altogether, this collection of reviews provides an important update on the state of the field, while also identifying new avenues of future research. We are grateful to all authors for their expert contributions, and hope that the readers of Transcription will treasure this issue focused on enhancers.