Regulatory Enhancer-Core-Promoter Communication via Transcription Factors and Cofactors

Abstract

Gene expression is regulated by genomic enhancers that recruit transcription factors and cofactors to activate transcription from target core promoters. Over the past years, thousands of enhancers and core promoters in animal genomes have been annotated, and we have learned much about the domain structure in which regulatory genomes are organized in animals. Enhancer-core-promoter targeting occurs at several levels, including regulatory domains, DNA accessibility, and sequence-encoded core-promoter specificities that are likely mediated by different regulatory proteins. We review here current knowledge about enhancer-core-promoter targeting, regulatory communication between enhancers and core promoters, and the protein factors involved. We conclude with an outlook on open questions that we find particularly interesting and that will likely lead to additional insights in the upcoming years.

Keywords: cofactors; core promoters; enhancers; enhancer–core-promoter specificity; transcription factors; transcription regulation.

Figure 1. Enhancers and core-promoters, two major classes of cis-regulatory elements.

An enhancer contains binding sites for sequence-specific transcription factors (TFs). These in turn recruit cofactors (COFs) that typically mediate the regulatory communication between the core promoter and the enhancer, i.e. relay the enhancer’s regulatory cues to the enhancer’s target core promoters. Core-promoters encompass short sequences of ~100bp surrounding the transcription start site, where Polymerase II (Pol II) assembles and initiates transcription. Core-promoters typically contain characteristic core-promoter elements or motifs, for example TATA box, Initiator or Downstream Promoter Element (DPE).

Figure 2. Topologically associating domains (TADs), promoter-proximal tethering elements (PTEs), and DNA accessibility.

(A) Enhancer function is typically restricted to activate core-promoters within the same TADs [12,31], the boundaries of which are enriched in insulator protein binding. (B) PTEs are sequences proximal to core-promoters that promote the preferential interaction between enhancers and core-promoters [–39]. For example, the PTE of the Sex combs reduced (Scr) core-promoter enables its activation by the distally-located Scr enhancer, skipping the intervening fushi tarazu (ftz). In transgenic reporter, relocation of the PTE to a proximal position of the ftz core-promoter results in activation of the latter by the Scr enhancer. In situ staining of embryo images are from Berkeley Drosophila Genome Project [161]. (C) Inaccessible DNA precludes a cis-regulatory element from participating in potential interaction. For example, Drosophila enhancers skip the proximal and inaccessible core-promoters, to activate more distal and accessible core-promoters [24].

Figure 3. Sequence-mediated enhancer–core-promoter specificity.

(A) housekeeping core promoters (hkCP; purple) show preferences towards housekeeping over developmental enhancers. The reverse is true for developmental core promoters (dCP; ochre; ref [60]). (B) housekeeping enhancers bind DREF and activate transcription from hkCP, which typically contain Ohler Motifs 1 and 6 core-promoter elements (indicated by motif logos). Developmental enhancers meanwhile bind Trl and activate transcription from dCPs that contain different core-promoter elements, such as TATA box, Initiator and DPE. Compared to housekeeping enhancers which are TSS-proximal or even overlapping, developmental enhancers are found at various positions, including within introns or very distal.

Figure 4. Trans factors mediate sequence-mediated enhancer–core-promoter specificity.

(A) Activator bypass experiments show that different transcription factors (TFs) and cofactors (COFs) can differentially active hkCP over dCP. Activation is indicated by a check mark and examples of TFs and cofactors that function accordingly are shown below. (B) hkCP and dCP recruit TRF2- and TBP-containing complexes, respectively. The members of these complexes also potentially differ.

Figure 5. Enhancers activate core-promoters in a microenvironment.

(A) Static model of transcription regulation in which defined protein complexes formed by static protein-protein interactions at enhancers exert their function on core promoters. This model is incompatible with some observations such as the simultaneous activation of two core-promoters by a single enhancer [123]. (B) Transcription regulation might alternatively occur via an activating microenvironment, in which enhancers and core-promoters recruit trans factors to create a high concentration of regulatory proteins that dynamically interact with each other, and enable regulatory communication through post-transcription modifications (PTMs, top) or dynamic protein-protein-interactions and recruitment (bottom).