From remote enhancers to gene regulation: charting the genome's regulatory landscapes

Abstract

Vertebrate genes are characterized by the presence of cis -regulatory elements located at great distances from the genes they control. Alterations of these elements have been implicated in human diseases and evolution, yet little is known about how these elements interact with their surrounding sequences. A recent survey of the mouse genome with a regulatory sensor showed that the regulatory activities of these elements are not organized in a gene-centric manner, but instead are broadly distributed along chromosomes, forming large regulatory landscapes with distinct tissue-specific activities. A large genome-wide collection of expression data from this regulatory sensor revealed some basic principles of this complex genome regulatory architecture, including a substantial interplay between enhancers and other types of activities to modulate gene expression. We discuss the implications of these findings for our understanding of non-coding transcription, and of the possible consequences of structural genomic variations in disease and evolution.

Constrained release of lamina-associated enhancers and genes from the nuclear envelope during T-cell activation facilitates their association in chromosome compartments

“…Thus, in all cases, the tighter regulation of these genes in resting lymphocytes from adding spatial control would benefit the organism. Similarly, regulating cis-regulatory elements such as enhancers is likely beneficial due to their ability to act on multiple target genes (Symmons and Spitz 2013). Importantly, the proximity of the A2 subcompartment into which they are released from the periphery would potentially enable regulation also in the opposite direction.…”

3D genomics imposes evolution of the domain model of eukaryotic genome organization

“…The integrity of these domains composed of several split regions is only reestablished as a result of 3D folding (Lonfat et al 2014). The identity of regulatory domains is determined by the coordinated action of numerous enhancers that may even be situated outside these domains (Marinic et al 2013;Symmons and Spitz 2013;Symmons et al 2014). Indeed, it is currently considered that tissue-specific gene expression is determined by enhancers rather than promoters (Heintzman et al 2009).…”

Understanding the Mechanisms Involved in the Regulation of Cytochrome P450 Gene Expression in Drosophila melanogaster (Diptera: Drosophilidae)

“…This level of regulation consolidates the contribution of various types of cis-acting genomic elements, which are vital molecular switches involved in the transcriptional regulation of a productive chain of gene activities regulating numerous biological processes, including abiotic stress responses, developmental processes and hormone responses [30,31]. This transcriptional regulation transpires within a complex genomic milieu in which promoters, enhancers, and insulators are intimately connected both along the one-dimensional linear chromosome and within the three-dimensional nuclear chromatin environment [32][33][34].…”

“…In variance with promoters, enhancers are typically located far away from the genes they regulate [31,32]. Albeit a promoter is utterly vital for gene transcription, a significant part of metazoan transcriptional regulation emanates via the action of distal cisregulatory modules [33,36].…”