Long-range chromosomal interactions regulate the timing of the transition between poised and active gene expression
Open accessAbstract
To understand how mammalian genes are regulated from their natural chromosomal environment, we have analysed the molecular events occurring throughout a 150 kb chromatin segment containing the alpha globin gene locus as it changes from a poised, silent state in erythroid progenitors, to the fully activated state in late, erythroid cells. Active transcription requires the late recruitment of general transcription factors, mediator and Pol II not only to the promoter but also to its remote regulatory elements. Natural mutants of the alpha cluster show that whereas recruitment of the pre-initiation complex to the upstream elements occurs independently, recruitment to the promoter is largely dependent on the regulatory elements. An improved, quantitative chromosome conformation capture analysis demonstrates that this recruitment is associated with a conformational change, in vivo, apposing the promoter with its remote regulators, consistent with a chromosome looping mechanism. These findings point to a general mechanism by which a gene can be held in a poised state until the appropriate stage for expression, coordinating the level and timing of gene expression during terminal differentiation.
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Active enhancers are often in physical proximity to the promoters they activate, regardless of the genomic distances between these enhancers and promoters.
“First, it was shown that active enhancers are often in physical proximity to the promoters they activate, regardless of the genomic distances between these enhancers and promoters [32,33,34].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [33]
The Discussion reports 3C evidence consistent with direct physical interaction between remote upstream regulatory elements and the α-globin promoter, with looping coinciding with transcription onset. The Introduction notes that regulatory elements can be tens or hundreds of kilobases from the genes they control. This supports long-range proximity in the studied locus, but not the broader claim that active enhancers are often close to their promoters regardless of genomic distance. (LLM, conf=0.84)
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Cites
Anguita, E., Hughes, J., Heyworth, C., Blobel, G. A., Wood, W. G., & Higgs, D. R. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600274 · Cited by 207 · see citing works
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Research works printed but not linked: 2
- Boehm AK, Saunders A, Werner J, Lis JT (2003) Transcription factor and polymerase recruitment, modification, and movement on dhsp70 in vivo in the minutes following heat shock. Mol Cell Biol 23: 7628-7637
- Plant KE, Routledge SJ, Proudfoot NJ (2001) Intergenic transcription in the human beta-globin gene cluster. Mol Cell Biol 21: 6507-6514
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Self-citationThe pluripotent regulatory circuitry connecting promoters to their long-range interacting elements
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Multiplexed analysis of chromosome conformation at vastly improved sensitivity
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Dynamics of the 4D Genome during in Vivo Lineage Specification and Differentiation
Oudelaar, A. M., Beagrie, R. A., Gosden, M., de Ornellas, S., Georgiades, E., Kerry, J., Hidalgo, D., Carrelha, J., Shivalingam, A., El-Sagheer, A. H., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16598-7 · Cited by 119 · see citing works
Self-citationLower, K. M., Hughes, J. R., De Gobbi, M., Henderson, S., Viprakasit, V., Fisher, C., Goriely, A., Ayyub, H., Sloane-Stanley, J., Vernimmen, D., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909331106 · Cited by 92 · see citing works
Self-citationChromosome conformation capture (from 3C to 5C) and its ChIP-based modification
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Enhancer Function in the 3D Genome
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- Authors
- Vernimmen, D., Gobbi, M. D., Sloane‐Stanley, J. A., Wood, W. G., & Higgs, D. R.
- Affiliations
- John Radcliffe Hospital (GB)
- Corresponding author
- Higgs, Douglas R
- Venue
- The EMBO Journal
- Published
- 2007-03-22
- Volume
- 26
- Issue
- 8
- Pages
- 2041-2051
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1852780
- OpenAlex
- W2162912283
- Cited by
- 244
- References
- 1
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 12 · 2020: 11 · 2019: 9 · 2018: 11 · 2017: 11 · 2016: 7 · 2015: 14 · 2014: 26 · 2013: 15 · 2012: 24
- FWCI
- 9.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Università degli Studi di Torino
- Medical Research Council
- 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 › Epigenetics and DNA Methylation
- Keywords
- chromatin looping, gene expression timing, erythroid differentiation, general transcription factors, Mediator complex, RNA polymerase II, chromatin conformation, terminal differentiation
- MeSH terms
- Animals, Chromosomes, Gene Expression Regulation, Globins, Models, Biological, Models, Molecular, Nucleic Acid Conformation, Erythroid Cells, Cell Line, Tumor, Chromatin Immunoprecipitation, Regulatory Elements, Transcriptional, Mice
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