Cohesin is required for long-range enhancer action
Open accessAbstract
Summary: The mammalian genome is organised into topologically associating domains (TADs) that are formed through the process of cohesin-driven loop extrusion 1–3 and whose extent is constrained at TAD boundaries by orientation-dependent CTCF binding 4–7 . The large regulatory landscapes of developmental genes frequently correspond to TADs, leading to the hypothesis that TADs and/or loop extrusion are important for enhancers to act on their cognate gene 8,9 . However, it has proven hard to interpret the consequences of experimental disruption of TADs or loop-extrusion on gene regulation 3,6,10 , in part because of the difficulty in distinguishing direct from indirect effects on enhancer-driven gene expression. By coupling acute protein degradation with synthetic activation by targeted transcription factor recruitment in mouse embryonic stem cells, here we show that cohesin, but not CTCF, is required for activation of a target gene by distant distal regulatory elements. Cohesin is not required for activation directly at the promoter or activation from an enhancer located closer to the gene. Our findings support the hypothesis that chromatin compaction mediated by cohesin-mediated loop extrusion allows for genes to be activated by regulatory elements that are located many hundreds of kilobases away in the linear genome but suggests that cohesin is dispensable for more genomically close enhancers.
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Cohesin-dependent enhancers tend to be longer-range than their cohesin-independent counterparts.
“Cohesin-dependent enhancers also tend to be longer-range than their cohesin-independent counterparts [301, 349, 514].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [514]
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Cites
Formation of chromosomal domains by loop extrusion
Fudenberg, G., Imakaev, M., Lu, C., Goloborodko, A., Abdennur, N., & Mirny, L. A. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.085 · Cited by 2,003 · see citing works
Cohesin Loss Eliminates All Loop Domains
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Multiscale 3D Genome Rewiring during Mouse Neural Development
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Self-citationCRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function
Guo, Y., Xu, Q., Canzio, D., Shou, J., Li, J., Gorkin, D. U., Jung, I., Wu, H., Zhai, Y., Tang, Y., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.038 · Cited by 958 · see citing works
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The cohesin release factor WAPL restricts chromatin loop extension
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Human cohesin compacts DNA by loop extrusion
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CTCF Binding Polarity Determines Chromatin Looping
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<i>Shh</i> and ZRS enhancer colocalisation is specific to the zone of polarising activity
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Aljahani, A., Hua, P., Karpinska, M. A., Quililan, K., Davies, J. O. J., & Oudelaar, A. M. (2022) · Nature Communications · doi:10.1038/s41467-022-29696-5 · Cited by 121 · see citing works
Transcriptional enhancers and their communication with gene promoters
Ray-Jones, H., & Spivakov, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03903-w · Cited by 81 · see citing works
- Authors
- Kane, L., Williamson, I., Flyamer, I. M., Kumar, Y., Hill, R. E., Lettice, L. A., & Bickmore, W. A.
- Affiliations
- Institute of Genetics and Cancer (GB)
- Corresponding author
- Bickmore, Wendy A.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2021-06-24
- OpenAlex
- W3174482644
- Cited by
- 23
- References
- 11
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 3 · 2022: 13 · 2021: 5
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Funders
- University of Oxford
- Medical Research Council (MC_UU_00007/8, MC_UU_00007/2)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- cohesin, topologically associating domains, loop extrusion, CTCF, chromatin condensation, distal regulatory elements, enhancer-gene interactions, mouse embryonic stem cells, transcription factor recruitment
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