A functional overlap between actively transcribed genes and chromatin insulator elements
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
- Douglas R. Higgs (ORCID: https://orcid.org/0000-0003-3579-8705)
- Matthew Gosden (ORCID: https://orcid.org/0000-0002-0657-7666)
- Lucy Cornell (ORCID: https://orcid.org/0000-0002-8561-5607)
- Mira T. Kassouf (ORCID: https://orcid.org/0000-0002-9781-921X)
- Rosa J. Stolper (ORCID: https://orcid.org/0000-0002-7890-7599)
- Benjamin Davies (ORCID: https://orcid.org/0000-0003-3623-600X)
- Damien J. Downes (ORCID: https://orcid.org/0000-0002-5034-0869)
- Caroline L. Harrold (ORCID: https://orcid.org/0000-0001-9140-0242)
- Felice Ho‐Ching Tsang (ORCID: https://orcid.org/0000-0002-7915-6782)
- Lars L. P. Hanssen (ORCID: https://orcid.org/0009-0003-0057-4565)
- Samy Alghadban
- J.R. Hughes
- Jacqueline A. Sloane-Stanley
- Jacqueline A. Sharpe
- Daniel Biggs
- Chris Preece
- Susannah Holliman
Institutions
- The Francis Crick Institute (GB)
- University of Oxford (GB)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Oxford Computer Services (United States) (US)
- MRC Human Immunology Unit (GB)
- Science Oxford (GB)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2026-03-16
- DOI
- https://doi.org/10.1038/s44318-026-00730-2
- Primary Topic
- Genomics and Chromatin Dynamics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Science Foundation
- Wellcome Trust
- UK Research and Innovation
- Chinese Academy of Medical Sciences
- Directorate for Biological Sciences
- Medical Research Council
- Biotechnology and Biological Sciences Research Council