No Need to Stick Together to Be Connected: Multiple Types of Enhancers' Networking

Simple Summary: Transcription 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.