Abstract
Simple SummaryTranscription regulation programs require the functional interaction of distal and proximal regulatory regions, interacting by specific 3D chromatin configurations. Enhancers are cis-acting regulatory elements able to promote gene expression regardless their orientation and distance from the transcription starting site. Their systematic mapping by genome-wide chromatin profiling and chromosome conformation analysis, combined with the development of gene-editing approaches to modulate their function, revealed that many enhancers work together to fine-tune the expression of their target genes. This review aim to describe the functions of different types of enhancers and the modalities of enhancers’ interaction, focusing on their role in the regulation of complex biological processes like cancer development.The control of gene expression at a transcriptional level requires a widespread landscape of regulatory elements. Central to these regulatory circuits are enhancers (ENHs), which are defined as cis-acting DNA elements able to increase the transcription of a target gene in a distance- and orientation-independent manner. ENHs are not independent functional elements but work in a complex and dynamic cooperative network, constituting the building blocks of multimodular domains of gene expression regulation. The information from each of these elements converges on the target promoter, contributing to improving the precision and sharpness of gene modulation. ENHs’ interplay varies in its nature and extent, ranging from an additive to redundant effect depending on contexts. Moving from super-enhancers that drive the high expression levels of identity genes, to shadow-enhancers, whose redundant functions contribute to buffering the variation in gene expression, this review aims to describe the different modalities of ENHs’ interaction and their role in the regulation of complex biological processes like cancer development.
Highlights
The human genome encodes the blueprint of human beings
The same happens in many diseases including cancer, in which evolution strongly relies on the aberrant reactivation of morphogenetic pathways [2]
Gene expression regulation has been considered as a mono-dimensional process in which each gene is controlled by the activity of the nearest promoter
Summary
The human genome encodes the blueprint of human beings. Cell fates and complex body plans are established through an elaborate succession of signals that define multidimensional and precise patterns of gene expression [1]. Central to the precise execution of these multidimensional circuitries are the enhancers (ENHs) [4] They have been classically described as cis-acting DNA elements that can increase the transcription of target genes by several magnitudes via their close three-dimensional space proximity with promoters [5,6,7]. Genetic approaches have demonstrated that multiple ENHs can converge on the regulation of a single gene, and that vice versa, a single ENH may simultaneously boost the transcription of multiple targets [19,20,21] These multiple regulatory interactions and their timing- and context-specificity dictate the execution of precise transcriptional programs defining cell-specific features. We report on the main features of the ENH networks and on the models that have been proposed to explain their function
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