Regulating specificity in enhancer–promoter communication

Galouzis, Charalampos Chrysovalantis; Furlong, Eileen E. M.

doi:10.1016/j.ceb.2022.01.010

Cited by 42 publications

(38 citation statements)

References 122 publications

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“…Erythroid super-enhancers activate and interact with their cognate promoters in a directional manner Within the confines of a topologically associating domain (TAD) or sub-TAD, it is thought that the direction of interaction and activity of any enhancer is determined to some extent by the molecular compatibility and distance between enhancers and their cognate promoters [22][23][24][25][26][37][38][39] . In addition, enhancer-promoter interactions may be affected by the distribution of other regulatory elements (e.g.…”

Section: Resultsmentioning

confidence: 99%

Multipartite super-enhancers function in an orientation-dependent manner

Kassouf

Francis

Gosden

et al. 2022

Preprint

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Transcriptional enhancers regulate gene expression in a developmental-stage and cell-specific manner. They were originally defined as individual regulatory elements that activate expression regardless of distance and orientation to their cognate genes. Genome-wide studies have shown that the mammalian enhancer landscape is much more complex, with different classes of individual enhancers and clusters of enhancer-like elements combining in additive, synergistic and redundant manners, possibly acting as single, integrated regulatory elements. These so-called super-enhancers are largely defined as clusters of enhancer-like elements which recruit particularly high levels of Mediator and often drive high levels of expression of key lineage-specific genes. Here, we analysed 78 erythroid-specific super-enhancers and showed that, as units, they preferentially interact in a directional manner, to drive expression of their cognate genes. Using the well characterised α -globin super-enhancer, we show that inverting this entire structure severely downregulates α -globin expression and activates flanking genes 5' of the super-enhancer. Our detailed genetic dissection of the α -globin locus clearly attributes the cluster's functional directionality to its sequence orientation, demonstrating that, unlike regular enhancers, super-enhancers act in an orientation-dependent manner. Together, these findings identify a novel emergent property of super-enhancers and revise current models by which enhancers are thought to contact and activate their cognate genes.

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Section: Resultsmentioning

confidence: 99%

Multipartite super-enhancers function in an orientation-dependent manner

Kassouf

Francis

Gosden

et al. 2022

Preprint

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“…However, enhancers often contain multiple transcription factor binding sites that are required for and control enhancer activity [ 52 ]. In addition, the enhancer could remotely regulate multiple genes expression via an enhancer-promoter loop [ 53 ]. Therefore, further research on the characteristics and functions of TIAM1 enhancer is required.…”

Section: Discussionmentioning

confidence: 99%

YAP1 induces invadopodia formation by transcriptionally activating TIAM1 through enhancer in breast cancer

et al. 2022

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Yes-associated protein 1 (YAP1), a central component of the Hippo pathway, plays an important role in tumor metastasis; however, the underlying mechanism remains to be elucidated. Invadopodia are actin-rich protrusions containing multiple proteases and have been widely reported to promote cell invasiveness by degrading the extracellular matrix. In the present study, we report that YAP1 induces invadopodia formation and promotes tumor metastasis in breast cancer cells. We also identify TIAM1, a guanine nucleotide exchange factor, as a target of the YAP1–TEAD4 complex. Our results demonstrate that YAP1 could promote TEAD4 binding to the enhancer region of TIAM1, which activates TIAM1 expression, subsequently increasing RAC1 activity and inducing invadopodia formation. These findings reveal the functional role of Hippo signaling in the regulation of invadopodia and provide potential molecular targets for preventing tumor metastasis in breast cancer.

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“…However, accumulating evidences indicate that additional factors (e.g. linear distance, CpG islands, promoter DNA methylation, type of core promoter elements) can also influence enhancer-gene compatibility within TADs (Arnold et al, 2017; Pachano et al, 2021; Ringel et al, 2021; Galouzis and Furlong, 2022; Zuin et al, 2022). As these factors are uncovered and characterized, they could be incorporated into POSTRE’s scoring system in order to further improve its specificity. POSTRE considers the cellular context to predict the pathological effects of SVs.…”

Section: Discussionmentioning

confidence: 99%

POSTRE: a tool to predict the pathological effects of human structural variants

Sánchez-Gaya

Rada-Iglesias

2022

Preprint

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Understanding the pathological impact of non-coding genetic variation is a major challenge in medical genetics. Accumulating evidences indicate that a significant fraction of genetic alterations, including structural variants (SVs), can cause human disease by altering the function of non-coding regulatory elements, such as enhancers. In the case of SVs, described pathomechanisms include changes in enhancer dosage and long-range enhancer-gene communication. However, there is still a clear gap between the need to predict and interpret the medical impact of non-coding variants, and the existence of tools to properly perform these tasks. To reduce this gap, we have developed POSTRE (Prediction Of STRuctural variant Effects), a computational tool to predict the pathogenicity of SVs implicated in a broad range of human congenital disorders. By considering disease-relevant cellular contexts, POSTRE identifies SVs with either coding or long range pathological consequences with high specificity and sensitivity. Furthermore, POSTRE not only identifies pathogenic SVs, but also predicts the disease-causative genes and the underlying pathological mechanism (e.g, gene deletion, enhancer disconnection, enhancer adoption, etc.). POSTRE is available at https://github.com/vicsanga/Postre.

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Regulating specificity in enhancer–promoter communication

Cited by 42 publications

References 122 publications

Multipartite super-enhancers function in an orientation-dependent manner

Multipartite super-enhancers function in an orientation-dependent manner

YAP1 induces invadopodia formation by transcriptionally activating TIAM1 through enhancer in breast cancer

POSTRE: a tool to predict the pathological effects of human structural variants

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