Developmental enhancers and chromosome topology

Abstract

Developmental enhancers mediate on/off patterns of gene expression in specific cell types at particular stages during metazoan embryogenesis. They typically integrate multiple signals and regulatory determinants to achieve precise spatiotemporal expression. Such enhancers can map quite far-one megabase or more-from the genes they regulate. How remote enhancers relay regulatory information to their target promoters is one of the central mysteries of genome organization and function. A variety of contrasting mechanisms have been proposed over the years, including enhancer tracking, linking, looping, and mobilization to transcription factories. We argue that extreme versions of these mechanisms cannot account for the transcriptional dynamics and precision seen in living cells, tissues, and embryos. We describe emerging evidence for dynamic three-dimensional hubs that combine different elements of the classical models.

Fig. 1.. Properties of enhancers influence the impact of TAD boundaries.

After boundary deletion (dashed lines), enhancers (E) have different abilities to regulate promoters in neighboring TADs depending on their (A) promiscuity, (B) promoter specificity, (C) distance to other promoters.

Fig. 2.. Models of enhancer-promoter communication.

(A) Pol II binds to an enhancer and tracks along chromatin (synthesizing RNA), pulling the enhancer with it. (B) TFs bound to a regulatory element oligomerize, chaining to the promoter. (C) Looping (in bacteria, lambda) requires protein-protein interactions between factors on the same face of the helix. (D) Long-range loops can bring enhancers close to a promoter, but not in direct proximity. Tracking or linking could bridge the distance.

Fig. 3.. Two types of topologies at complex loci.

(A) Left: Enhancer (E)–promoter proximity at the time of gene expression. Right: Preformed (compacted) topologies prior to gene expression. (B) Insulator:insulator pairing brings transgenic eve-promoter and endogenous enhancers (E) in proximity—from ~700 to ~400 nm, without lacZ-reporter transcription. (C) Further compaction (~335 nm) occurs during reporter transcription.

Fig. 4.. Hub and condensates model.

Preformed topologies increase local TF, coactivator, and Pol II concentration (hubs or microenvironments), where different enhancers (E) dynamically share common resources.