A gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker

Yavor K. Bozhilov, Damien J. Downes, Jelena Telenius, A. Marieke Oudelaar, Emmanuel N. Olivier, Joanne C. Mountford, Jim R. Hughes, Richard J. Gibbons () and Douglas R. Higgs ()
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Yavor K. Bozhilov: University of Oxford
Damien J. Downes: University of Oxford
Jelena Telenius: University of Oxford
A. Marieke Oudelaar: The Max Planck Institute for Biophysical Chemistry
Emmanuel N. Olivier: Albert Einstein College of Medicine, Department of Cell Biology
Joanne C. Mountford: University of Glasgow
Jim R. Hughes: University of Oxford
Richard J. Gibbons: University of Oxford
Douglas R. Higgs: University of Oxford

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Many single nucleotide variants (SNVs) associated with human traits and genetic diseases are thought to alter the activity of existing regulatory elements. Some SNVs may also create entirely new regulatory elements which change gene expression, but the mechanism by which they do so is largely unknown. Here we show that a single base change in an otherwise unremarkable region of the human α-globin cluster creates an entirely new promoter and an associated unidirectional transcript. This SNV downregulates α-globin expression causing α-thalassaemia. Of note, the new promoter lying between the α-globin genes and their associated super-enhancer disrupts their interaction in an orientation-dependent manner. Together these observations show how both the order and orientation of the fundamental elements of the genome determine patterns of gene expression and support the concept that active genes may act to disrupt enhancer-promoter interactions in mammals as in Drosophila. Finally, these findings should prompt others to fully evaluate SNVs lying outside of known regulatory elements as causing changes in gene expression by creating new regulatory elements.

Date: 2021
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DOI: 10.1038/s41467-021-23980-6

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