Transcriptional Regulation by (Super)Enhancers: From Discovery to Mechanisms

Abstract

Accurate control of gene expression in the right cell at the right moment is of fundamental importance to animal development and homeostasis. At the heart of gene regulation lie the enhancers, a class of gene regulatory elements that ensures precise spatiotemporal activation of gene transcription. Mammalian genomes are littered with enhancers, which are frequently organized in cooperative clusters such as locus control regions and superenhancers. Here, we discuss our current knowledge of enhancer biology, including an overview of the discovery of the various enhancer subsets and the mechanistic models used to explain their gene regulatory function. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 22 is August 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Transcriptional enhancers and their communication with gene promoters

“…Enhancers were first described around 20 years after the discovery of the gene promoter [1][2][3][4][5][6][7]. In 1980, the first evidence for enhancers arose when short DNA sequences were discovered within the simian virus 40 (SV40) [2] and the sea urchin genome [3] that were remote from a gene promoter, yet seemed to stimulate gene expression by an unknown mechanism.…”

Context-Dependent Enhancer Function Revealed by Targeted Inter-TAD Relocation

“…On the other hand, both HOXD13 and HOXA13 proteins contain a large poly-alanine stretch (Bruneau et al, 2001), which may potentially drive the formation of phase-separated globules by co-condensing with transcriptional co-activators/co-repressors, as shown for these and other genes (Basu et al, 2020; Grosveld et al, 2021). It is thus possible that, due to their high content in bound HOX13 proteins, which contain stretches of poly-alanine (Bruneau et al, 2001), both C-DOM and T-DOM are used to form large transcription-hub condensate (Grosveld et al, 2021)(Amândio et al, 2020), leading to a positive transcriptional outcome for C-DOM in distal limb cells, and a negative outcome for T-DOM, within the same cells, due to the inclusion of additional co-factors that are specific to each domain (Karr et al, 2021). This latter explanatory framework would also account for why the deletion of the enhancer II1 in vivo had essentially no detectable effect upon transcription of target Hoxd genes in distal limbs, much like what was reported for C-DOM enhancers used for external genitals (Amândio et al, 2020) as well as in other comparable instances (Osterwalder et al, 2018).…”

“…Within these landscapes, gene activation can be distributed across multiple enhancers (Marinic et al, 2013; Montavon et al, 2011) often leading to functional redundancy between them or to more complex interactions (Amândio et al, 2020; Osterwalder et al, 2018). Alternatively, enhancer sequences can be grouped together in a more compact manner, either to ensure a coordinated function, as exemplified by the Globin genes (Grosveld et al, 2021; Liu et al, 2018; Oudelaar et al, 2021), or to maximize transcription in a given cellular context such as the compact regulatory structure referred to as super enhancers (Blobel et al, 2021; Hnisz et al, 2013).…”

“…On the one hand, these factors may bind to and activate an enhancer-reporter transgene in a sequence-specific manner, as many transcription factors do, leading to the pattern described herein and its absence in transgenes lacking the binding sites. On the other hand, both HOXD13 and HOXA13 proteins contain a large poly-alanine stretch (Bruneau et al, 2001), which may potentially drive the formation of phase-separated globules by co-condensing with transcriptional co-activators/co-repressors, as shown for these and other genes (Basu et al, 2020; Grosveld et al, 2021). It is thus possible that, due to their high content in bound HOX13 proteins, which contain stretches of poly-alanine (Bruneau et al, 2001), both C-DOM and T-DOM are used to form large transcription-hub condensate (Grosveld et al, 2021)(Amândio et al, 2020), leading to a positive transcriptional outcome for C-DOM in distal limb cells, and a negative outcome for T-DOM, within the same cells, due to the inclusion of additional co-factors that are specific to each domain (Karr et al, 2021).…”

An RNA Polymerase III General Transcription Factor Engages in Cell Type-Specific Chromatin Looping

“…The first two classes of TFs can be expressed ubiquitously or be cell type-specific factors (CTFs), whereas GTFs are expressed in every single cell of the organism [2][3][4]. The actions of CTFs are largely studied and depend on the overwhelming number of distinct and specific DNA binding sites on regulatory regions, either in the promoter regions or tens to hundreds of kilobases away from the promoters they activate [5][6][7]. The latter are known as enhancers and/or super-enhancers and they are referred to as regulatory distal enhancers elements (DEEs).…”