Enhancer redundancy in development and disease

Abstract

Shadow enhancers are seemingly redundant transcriptional cis-regulatory elements that regulate the same gene and drive overlapping expression patterns. Recent studies have shown that shadow enhancers are remarkably abundant and control the majority of developmental gene expression in both invertebrates and vertebrates, including mammals. Shadow enhancers might provide an important mechanism for buffering against mutations in non-coding regulatory regions of genes implicated in human disease. Technological advances in genome editing and live imaging have shed light on how shadow enhancers establish precise gene expression patterns and confer phenotypic robustness. Shadow enhancers can interact in complex ways and may also help drive the formation of transcriptional hubs within the nucleus. Despite their apparent redundancy, the prevalence and evolutionary conservation of shadow enhancers underscore their key role in emerging metazoan gene regulatory networks.

A YY1 phosphorylation switch in brown adipose tissue orchestrates energy homeostasis.

“…Multiple transcription factors or co-activators are known to control nutrient sensing and metabolism and the robustness of gene expression regulation is maintained through transcription factor redundancy (Kvon et al, 2021). We suggest here that YY1 exerts a basal but necessary layer of transcriptional regulation for specific metabolic transcription factors.…”

Cell-specific alterations inPitx1regulatory landscape activation caused by the loss of a single enhancer

“…Alteration in the enhancer composition of regulatory landscapes at developmental genes can lead to pathologies by modifying the dosage and/or distribution of genes transcription (Kvon et al 2021).…”

“…Alteration in the enhancer composition of regulatory landscapes at developmental genes can lead to pathologies by modifying the dosage and/or distribution of genes transcription (Kvon et al 2021). Indeed, over the past years, loss of single regulatory units within complex and partially redundant regulatory landscapes were shown to have clear phenotypical outcomes despite inducing only partial decreases in average transcription (Montavon et al 2011; Will et al 2017; Osterwalder et al 2018).…”

Differential regulation of alternative promoters emerges from unified kinetics of enhancer-promoter interaction

“…The differential expression of these isoforms is critical to important biological processes (Lu et al, 2020;Pozner et al, 2007). Misregulation of these isoforms can lead to diseases, including cancer (Davuluri et al, 2008;de Klerk and t Hoen, 2015;Kvon et al, 2021;Sendoel et al, 2017). Thus, eukaryotic gene regulation needs to be understood at the level of individual alternative promoters and enhancers.…”

“…Alternatively, different enhancers may be mutually exclusive and compete for promoter activation (Bothma et al, 2015;Scholes et al, 2019). In these cases, enhancers combine their regulatory effects differently, ranging from superadditive to subadditive or even repressive summation (Kvon et al, 2021). Similarly, a single enhancer may activate multiple promoters simultaneously (Fukaya et al, 2016;Lim et al, 2018) or one at a time (Su et al, 1991).…”