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Review
. 2021 Jan 12;22(2):671.
doi: 10.3390/ijms22020671.

Mechanisms of Enhancer-Promoter Interactions in Higher Eukaryotes

Olga Kyrchanova  1 , Pavel Georgiev  1
Affiliations
Review

Mechanisms of Enhancer-Promoter Interactions in Higher Eukaryotes

Olga Kyrchanova et al. Int J Mol Sci. .

Abstract

In higher eukaryotes, enhancers determine the activation of developmental gene transcription in specific cell types and stages of embryogenesis. Enhancers transform the signals produced by various transcription factors within a given cell, activating the transcription of the targeted genes. Often, developmental genes can be associated with dozens of enhancers, some of which are located at large distances from the promoters that they regulate. Currently, the mechanisms underlying specific distance interactions between enhancers and promoters remain poorly understood. This review briefly describes the properties of enhancers and discusses the mechanisms of distance interactions and potential proteins involved in this process.

Keywords: C2H2 proteins; CTCF; LDB1; chromatin insulator; long-distance interactions.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the transcriptional complexes involved in enhancer activity. Various transcription factors (TFs) bind to enhancer sites and recruit complexes involved in transcription stimulation. p300/CBP possesses acetyltransferase activity and is responsible for H3K27 acetylation. The Mll3/4 complexes induce H3K4 monomethylation and recruit the UTX demethylase, which can remove the H3K27me3 generated by the PRC2 complex and associated with repressed chromatin. p300/CBP, Mll3/4, and UTX are thought to regulate transcription and enhancer activity through the modification of currently unknown components of transcriptional complexes on promoters. The subunits of the mediator complex form three main modules: head, middle, and tail. The mediator complex is recruited to the enhancer via multiple interactions between subunits of the tail module and the intrinsically disordered regions of TFs.
Figure 2
Figure 2
Models showing the remote activation of a promoter by an enhancer. (A) Classical model of enhancer-promoter communication. The interaction between an enhancer and a promoter can be stabilized by CCCTC-binding factor (CTCF), in cooperation with the cohesin complex and the dimerization of LOB domain-containing protein 1 (LDB1), which is recruited to chromatin through interactions with LIM proteins. The TFs bind to the enhancer and a promoter to form a platform for the transient recruitment of the mediator complex. The mediator complex transfers RNA polymerase II to the promoter transcription factor IID (TFIID) complex and accelerates further transcription initiation steps to induce a short transcriptional pulse (burst). The enhancer strength is directly correlated with the efficiency of mediator recruitment to chromatin. (B) Model of enhancer-promoter communication through the formation of hubs. Interactions between CTCF/cohesion sites form domains in which enhancers and promoters are located relatively close to each other. TF activation domains associated with enhancers usually contain internally disordered regions that can efficiently interact with subunits of the Mediator and RNA polymerase II complexes. As a result, the concentration of transcriptional complexes increases near enhancers, and promoters can more efficiently recruit these complexes to initiate transcription.
Figure 3
Figure 3
(A) Schematic representation of mammalian proteins involved in the formation of chromosome architecture. LDB1 contains LDB/Chip conserved domain (LCCD) that interacts with several DNA binding proteins including CTCF. (B) CTCF/cohesin loop formation model. (C) Model of LDB1-mediated enhancer-promoter interaction.
Figure 4
Figure 4
Model of the formation of highly specific transcription hub by OSN enhancers. (A) In progenitor cell, all OR genes are weakly co-expressed. (B) During OSN maturation, transcription of one OR gene is activated randomly, while all others remain completely suppressed. The OR genes are enriched in chromatin marks (H3K9me3, H3K20me3) associated with transcriptional repression. The transcriptionally active OR promoter, labeled H3K4me3, is associated with a hub formed by enhancers enriched in the Edf and Lhx2 proteins and nucleosomes marked by H3K4me1 and H3K27Ac. (C) The LDB1 protein recruited by Lhx2 is involved in the organization of hub formed by OSN enhancers located on different chromosomes. It seems likely that other unknown architectural proteins are involved in hub formation in cooperation with LDB1.
Figure 5
Figure 5
Model of interaction between regulatory elements in Drosophila. Architectural C2H2 proteins bind in different combinations to regulatory elements (promoters, enhancers, insulators). The CP190 and Mod(mdg4) and other similar proteins with homodimerization domains are recruited on the regulatory elements through interaction with C2H2 proteins. (A) Super-long-distance interactions are supported by multiple interactions between 3–6 C2H2 proteins associated with the same or structurally similar insulators. The interactions between proteins like Mod(mdg4) and CP190 can play a role in maintaining of stable interaction. (B) Specific distance interactions (5–20 kb) can be supported by regulatory elements that contain only partially similar combinations of C2H2 proteins. The auxiliary CP190 and Mod(mdg4) can play an important role in maintaining remote communications in such cases. (C) Local interactions between regulatory elements can be supported by proteins such as CP190 and Mod(mdg4), which can be recruited to completely different combinations of C2H2 proteins.
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