Integrative approaches to study enhancer-promoter communication

Abstract

The spatiotemporal control of gene expression in complex multicellular organisms relies on noncoding regulatory sequences such as enhancers, which activate transcription of target genes often over large genomic distances. Despite the advances in the identification and characterization of enhancers, the principles and mechanisms by which enhancers select and control their target genes remain largely unknown. Here, we review recent interdisciplinary and quantitative approaches based on emerging techniques that aim to address open questions in the field, notably how regulatory information is encoded in the DNA sequence, how this information is transferred from enhancers to promoters, and how these processes are regulated in time.

Figure 1

Enhancer-promoter (E-P) communication and transcriptional outputs depend on a number of variables, including enhancer and promoter sequence, number, and mutual genomic distance, in a way that depends on binding of TFs and interactions with cofactors, the physical proximity between regulatory sequences and their dynamics.

Figure 2

Two alternative (and not mutually exclusive) potential mechanisms of information transfer from enhancers to promoters. Information might be passed on to the promoter through direct interactions between TFs and cofactors, or through local enrichment of TFs and cofactors in the vicinity of the promoter. Both mechanisms must result in the transfer of information being used by the promoter to enhance PolII recruitment, post-transcriptional modifications, or events leading to transcriptional initiation or elongation (PTM=post-translational modifications).

Figure 3

Temporal dynamics of E–P communication. (a) Transcription initiation and the resulting transcriptional bursts are preceded by multiple processes, notably fast TF and cofactor binding (typically in the second to tens-of-seconds range) and looping of the chromatin fiber that establishes physical proximity, recently suggested to occur on the order of minutes. (b) While TF-binding dynamics are fast and occur frequently, possibly enabling continuous occupancy of TFBS at the enhancer and the promoter, E–P proximity is presumably longer and occurs less frequently, leading to potential models of E–P communication in time: i) one interaction might lead to one event of transcription initiation, ii) possibly with a delay, or alternatively more complicated scenarios iii) where one initiation event can only be achieved by multiple consecutive interaction events.