The α-globin super-enhancer acts in an orientation-dependent manner

Mira T. Kassouf (mira.kassouf@imm.ox.ac.uk), Helena S. Francis, Matthew Gosden, Maria C. Suciu, Damien J. Downes, Caroline Harrold, Martin Larke, Marieke Oudelaar, Lucy Cornell, Joseph Blayney, Jelena Telenius, Barbara Xella, Yuki Shen, Nikolaos Sousos, Jacqueline A. Sharpe, Jacqueline Sloane-Stanley, Andrew J. H. Smith, Christian Babbs, Jim R. Hughes and Douglas R. Higgs (doug.higgs@imm.ox.ac.uk)
Additional contact information
Mira T. Kassouf: John Radcliffe Hospital
Helena S. Francis: John Radcliffe Hospital
Matthew Gosden: John Radcliffe Hospital
Maria C. Suciu: John Radcliffe Hospital
Damien J. Downes: John Radcliffe Hospital
Caroline Harrold: John Radcliffe Hospital
Martin Larke: John Radcliffe Hospital
Marieke Oudelaar: Max Planck Institute for Multidisciplinary Sciences
Lucy Cornell: John Radcliffe Hospital
Joseph Blayney: John Radcliffe Hospital
Jelena Telenius: John Radcliffe Hospital
Barbara Xella: John Radcliffe Hospital
Yuki Shen: John Radcliffe Hospital
Nikolaos Sousos: John Radcliffe Hospital
Jacqueline A. Sharpe: John Radcliffe Hospital
Jacqueline Sloane-Stanley: John Radcliffe Hospital
Andrew J. H. Smith: University of Edinburgh
Christian Babbs: John Radcliffe Hospital
Jim R. Hughes: John Radcliffe Hospital
Douglas R. Higgs: John Radcliffe Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56380-1

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