Emerging similarities between regulatory elements

Mammalian transcription is controlled by a complex interplay of regulatory events. Together, these events determine the correct spatio-temporal initiation and rate of RNA polymerase II (RNAPII) gene transcription.

Several decades of research on transcriptional regulation have identified different modes of regulation that have been ascribed to distinct regulatory elements – stretches of DNA with specific information and genomic locations needed for their tasks. Core promoters are located at transcription initiation sites and carry binding sites to general transcription factors that help recruit and assemble the RNAPII machinery. The activation, rate of initiation and elongation are further influenced by promoter-distal regulatory elements called enhancers – elements that are generally believed to be the main determinants of cell-type-specific and precise developmental gene expression. Silencers – elements that bind repressors that block transcription – or insulators – boundary elements that block the interplay between promoters and enhancers or silencers, further add to the complex landscape of transcriptional regulation.

Incorrect spatio-temporal regulation of gene expression may lead to disease. This is one of the main motivations behind increased efforts to characterize the locations and cell-type-specific activities of regulatory elements in mammalian genomes. While the genomic locations of gene promoters may be inferred using various RNA sequencing techniques, other kinds of regulatory elements have been harder to localize. Major consortia such as the The Encyclopedia of DNA Elements (ENCODE) and the NIH Roadmap Epigenomics Mapping Consortium have therefore invested a considerable amount of time and resources to delineate rules on how to localize and infer the activities of regulatory elements.

However, recent studies have generated data that question the fundamental separation of regulatory elements into distinct entities. Transcription initiation occurs at enhancers (see also related post). This property does not only enable precise localization of enhancers; it is also a good predictor of their regulatory activities. Hence, the activity of an enhancer may be inferred by a property that is generally ascribed promoters. Adding to their similarities, gene promoters can have enhancer activities and a considerable fraction of DNA sequences with enhancer potential overlap core promoters in Drosophila.

I discuss the similarities between enhancers and promoters in a recent opinion paper [1]. Together with Albin Sandelin and Charles Danko, we take this one step further and suggest a unified architecture of transcriptional regulatory elements [2]. I am now happy to see that also Tae-Kyung Kim and Ramin Shiekhattar recognize the similarities between enhancers and promoters and the problems with their distinctions [3].

Similarities between regulatory elements have been discussed also elsewhere in the literature. Jesse Raab and Rohinton Kamakaka discuss the apparent similarities between insulators and promoters [4]. Alexander Feuerborn and Peter Cook suggest a unifying view of regulatory elements and that regulatory function is determined by the three-dimensional structure of chromatin and selective tethering of transcription units to transcription factories [5].

Taken together, recent observations call for a reconsideration of current discriminatory rules of regulatory elements. In light of recent data, regulatory elements should not generally be considered distinct entities but rather elements with varying functions. The functions of regulatory elements seem to be context dependent and determined by the physical proximity of other regulatory elements and their bound factors.

  1. Andersson R. Promoter or enhancer, what’s the difference? Deconstruction of established distinctions and presentation of a unifying model. Bioessays. 2015 Mar;37(3):314-23.
  2. Andersson R, Sandelin A, Danko CG. A unified architecture of transcriptional regulatory elements. Trends Genet. 2015 Aug;31(8):426-33.
  3. Kim T-K, Shiekhattar R. Architectural and Functional Commonalities between Enhancers and Promoters. Cell. 2015;162(5): 948-59.
  4. Raab JR, Kamakaka RT. Insulators and promoters: closer than we think. Nat Rev Genet. 2010 Jun;11(6):439-46.
  5. Feuerborn A, Cook PR. Why the activity of a gene depends on its neighbors. Trends Genet. 2015 Aug 7.