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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.Competing Interest StatementJ.R.H. is a founder and shareholder of Nucleome Therapeutics; J.R.H., and D.J.D. are paid consultants for Nucleome Therapeutics. J.R.H. holds patents for Capture-C (nos. WO2017068379A1, EP3365464B1 and US10934578B2). These authors declare no other financial or non-financial interests. The remaining authors declare no competing interests.

Original publication

DOI

10.1101/2022.07.14.499999

Type

Journal article

Journal

bioRxiv

Publisher

Cold Spring Harbor Laboratory

Publication Date

2022