A functional overlap between actively transcribed genes and chromatin insulator elements
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Lucy J Cornell Caroline L Harrold Susannah Holliman Felice Tsang Matthew E Gosden Lars LP Hanssen Rosa Stolper Damien J Downes Daniel Biggs Chris Preece Samy Alghadban Jacqueline A Sharpe Ben Davies Jacqueline A Sloane-Stanley Jim R Hughes Douglas R Higgs Mira T KassoufAbstract
The mammalian genome is organised into large topologically associating domains (TADs) and smaller sub-TADs or enhancer-promoter loops, which may contribute to the regulation of gene expression. These dynamic structures arise, at least partly, via cohesin-mediated loop extrusion delimited by insulator elements. By studying the structure and function of the alpha-globin locus during erythroid differentiation, we have previously shown that the juxtaposition of the enhancers and promoters during this process partly depends on cohesin-mediated loop extrusion, which appears to be delimited by 12 largely convergently orientated CTCF boundary elements. To define the downstream boundary of the sub-TAD, we removed four CTCF sites in informative combinations. This showed that rather than CTCF insulators, it is the transcriptionally active alpha-globin gene that defines the downstream boundary of the sub-TAD. Further, insertion of actively transcribed fragments of the α-globin gene between the enhancers and native genes leads to a reduction in native α-globin expression and accumulation of cohesin at the insertion site. This highlights an overlap in the functional role of the fundamental elements of the genome.
Journal details
Journal
EMBO Journal
Volume
45
Issue number
8
Pages
2587-2613
Available online
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10.1038/s44318-026-00730-2
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Europe PubMed Central
41840057
Pubmed
41840057
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