A functional overlap between actively transcribed genes and chromatin insulator elements

Journal article

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.

Authors: Cornell, LJ; Harrold, CL; Holliman, S; Tsang, F; Gosden, ME

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: EMBO Press
• Journal: The EMBO Journal
• Volume: 45
• Issue: 8
• Pages: 2587-2613
• Publication date: 2026-03-16
• Acceptance date: 2026-01-21
• DOI: 10.1038/s44318-026-00730-2
• EISSN: 1460-2075
• ISSN: 0261-4189
• Language: English
• Keywords: Insulators; Regulation; Domains; CTCF; Transcription