The α-globin super-enhancer acts in an orientation-dependent manner
Kassouf MT., Francis HS., Gosden M., Suciu MC., Downes DJ., Harrold C., Larke M., Oudelaar M., Cornell L., Blayney J., Telenius J., Xella B., Shen Y., Sousos N., Sharpe JA., Sloane-Stanley J., Smith AJH., Babbs C., Hughes JR., Higgs DR.
Abstract Individual enhancers are defined as short genomic regulatory elements, bound by transcription factors, and able to activate cell-specific gene expression at a distance, in an orientation-independent manner. Within mammalian genomes, enhancer-like elements may be found individually or within clusters referred to as locus control regions or super-enhancers (SEs). While these behave similarly to individual enhancers with respect to cell specificity, distribution and distance, their orientation-dependence has not been formally tested. Here, using the α-globin locus as a model, we show that while an individual enhancer works in an orientation-independent manner, the direction of activity of a SE changes with its orientation. When the SE is inverted within its normal chromosomal context, expression of its normal targets, the α-globin genes, is severely reduced and the normally silent genes lying upstream of the α-globin locus are upregulated. These findings add to our understanding of enhancer-promoter specificity that precisely activate transcription.