Enhancer-Promoter Communication: It’s Not Just About Contact

Abstract

Cis-regulatory elements such as enhancers can be located even a million base pairs away from their cognate promoter and yet modulate gene transcription. Indeed, the 3D organisation of chromatin enables the establishment of long-range enhancer-promoter communication. The observation of long-range enhancer-promoter chromatin loops at active genes originally led to a model in which enhancers and promoters form physical contacts between each other to control transcription. Yet, recent microscopy data has challenged this prevailing activity-by-contact model of enhancer-promoter communication in transcriptional activation. Live single-cell imaging approaches do not systematically reveal a correlation between enhancer-proximity and transcriptional activation. We therefore discuss the need to move from a static to a dynamic view of enhancer-promoter relationships. We highlight recent studies that not only reveal considerable chromatin movement in specific cell types, but suggest links between chromatin compaction, chromatin movement and transcription. We describe the interplay between enhancer-promoter proximity within the context of biomolecular condensates and the need to understand how condensate microenvironments influence the chromatin binding kinetics of proteins that bind at cis-regulatory elements to activate transcription. Finally, given the complex multi-scale interplay between regulatory proteins, enhancer-promoter proximity and movement, we propose the need to integrate information from complementary single-cell next-generation sequencing and live-cell imaging approaches to derive unified 3D theoretical models of enhancer-promoter communication that are ultimately predictive of transcriptional output and cell fate. In time, improved models will shed light on how tissues grow and diseases emerge.

De novo lipogenesis pathway is a vulnerability in IDH1 mutant glioma

“…Interestingly, a recent study using human primary cells showed VPA promoted both histone acetylation and deacetylation, and the increase in histone acetylation with VPA is regional 23 . The increase in gene expression with VPA as we observed in our glioma cell lines may be driven by alternate promoters 24 or complex interaction between promoter and enhancers 25 .…”

Shared and distinct molecular effects of regulatory genetic variants provide insight into mechanisms of distal enhancer-promoter communication

“…The transfer of activating signals from distal enhancers to promoters typically (though not always) depends on connections between these elements within the nucleus. These connections can be established through direct 3D chromosomal contacts or potentially through other mechanisms, such as phase separation [3][4][5][6] . Previous studies that compared the dynamics of enhancer activation, enhancer-promoter connections and gene expression across cell types and conditions have found that these events are often correlated, although cases whereby enhancerpromoter contacts precede enhancer activation and gene induction are also common 4,[7][8][9][10] .…”

UV-induced reorganization of 3D genome mediates DNA damage response

“…These points represent ‘loops’, and may manifest individually or as components of grids, often found at domain corners. Accordingly, chromatin loops are considered the primary mechanism of enhancer-promoter interactions facilitated upon cohesin-mediated loop extrusion accompanied with barrier elements [45,46,47]. A chromatin loop consists of a pair of proximal regions, referred as loop anchors.…”