Long-range chromatin regulatory interactions in vivo
Abstract
Communication between distal chromosomal elements is essential for control of many nuclear processes. For example, genes in higher eukaryotes often require distant enhancer sequences for high-level expression. The mechanisms proposed for long-range enhancer action fall into two basic categories. Non-contact models propose that enhancers act at a distance to create a favorable environment for gene transcription, or act as entry sites or nucleation points for factors that ultimately communicate with the gene. Contact models propose that communication occurs through direct interaction between the distant enhancer and the gene by various mechanisms that 'loop out' the intervening sequences. Although much attention has focused on contact models, the existence and nature of long-range interactions is still controversial and speculative, as there is no direct evidence that distant sequences physically interact in vivo. Here, we report the development of a widely applicable in situ technique to tag and recover chromatin in the immediate vicinity of an actively transcribed gene. We show that the classical enhancer element, HS2 of the prototypical locus control region (LCR) of the beta-globin gene cluster, is in close physical proximity to an actively transcribed HBB (beta-globin) gene located over 50 kb away in vivo, suggesting a direct regulatory interaction. The results give unprecedented insight into the in vivo structure of the LCR-gene interface and provide the first direct evidence of long-range enhancer communication.
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Two papers published in 2002 used different novel biochemical techniques to demonstrate that the β-globin LCR forms chromosomal loops with the active β-globin genes in vivo.
“Two papers published in 2002 used different novel biochemical techniques to demonstrate that the β-globin LCR forms chromosomal loops with the active β-globin genes in vivo.”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [265]
In erythroid cells, the locus control region (LCR) is in physical proximity to the β-globin genes in a developmentally dynamic manner.
“In erythroid cells, a powerful distal enhancer called the locus control region (LCR), composed of multiple DNase I hypersensitive sites (HSs), is in physical proximity to the β-globin genes in a developmentally dynamic manner (Carter et al., 2002; Tolhuis et al., 2002).”
From Reactivation of developmentally silenced globin genes by forced chromatin looping (2014) · cites this paper as Carter et al., 2002
Central to the mechanism of globin gene switching is the exclusive interaction between the LCR and globin gene promoters at distinct developmental stages.
“Central to the mechanism of globin gene switching is the exclusive interaction between the LCR and globin gene promoters at distinct developmental stages (Carter et al., 2002; Palstra et al., 2008; Tolhuis et al., 2002).”
From Reactivation of developmentally silenced globin genes by forced chromatin looping (2014) · cites this paper as Carter et al., 2002
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- Authors
- Carter, D., Chakalova, L., Osborne, C. S., Dai, Y.-F., & Fraser, P.
- Affiliations
- Babraham Institute (GB)
- Corresponding author
- Fraser, Peter
- Venue
- Nature Genetics
- Published
- 2002-11-11
- Volume
- 32
- Issue
- 4
- Pages
- 623-626
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2020977773
- Cited by
- 663
- References
- 24
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 13 · 2023: 17 · 2022: 16 · 2021: 23 · 2020: 12 · 2019: 26 · 2018: 25 · 2017: 19 · 2016: 18 · 2015: 20 · 2014: 19 · 2013: 23 · 2012: 43
- FWCI
- 14.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- 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 › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- long-range chromatin interactions, enhancer-promoter interactions, locus control region, beta-globin gene cluster, beta-globin gene, chromatin looping, gene expression regulation
- MeSH terms
- Animals, Binding Sites, Chromatin, Deoxyribonuclease I, Embryo, Mammalian, Enhancer Elements, Genetic, Globins, Introns, Liver, Mice, Inbred BALB C, Models, Genetic, RNA, Messenger, Transcription, Genetic, Polymerase Chain Reaction, In Situ Hybridization, Fluorescence, Gene Expression Regulation, Developmental, Locus Control Region, Oligonucleotide Array Sequence Analysis, Mice
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