A tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions
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Abstract
A variety of self-interacting domains, defined at different levels of resolution, have been described in mammalian genomes. These include Chromatin Compartments (A and B) 1 , Topologically Associated Domains (TADs) 2,3 , contact domains 4,5 , sub-TADs 6 , insulated neighbourhoods 7 and frequently interacting regions (FIREs) 8 . Whereas many studies have found the organisation of self-interacting domains to be conserved across cell types 3 8 9 , some do form in a lineage-specific manner 6710 . However, it is not clear to what degree such tissue-specific structures result from processes related to gene activity such as enhancer-promoter interactions or whether they form earlier during lineage commitment and are therefore likely to be prerequisite for promoting gene expression. To examine these models of genome organisation in detail, we used a combination of high-resolution chromosome conformation capture, a newly-developed form of quantitative fluorescence in-situ hybridisation and super-resolution imaging to study a 70 kb self-interacting domain containing the mouse α-globin locus. To understand how this self-interacting domain is established, we studied the region when the genes are inactive and during erythroid differentiation when the genes are progressively switched on. In contrast to many current models of long-range gene regulation, we show that an erythroid-specific, decompacted self-interacting domain, delimited by convergent CTCF/cohesin binding sites, forms prior to the onset of robust gene expression. Using previously established mouse models we show that formation of the self-interacting domain does not rely on interactions between the α-globin genes and their enhancers. As there are also no tissue-specific changes in CTCF binding, then formation of the domain may simply depend on the presence of activated lineage-specific cis-elements driving a transcription-independent mechanism for opening chromatin throughout the 70 kb region to create a permissive environment for gene expression. These findings are consistent with a model of loop-extrusion in which all segments of chromatin, within a region delimited by CTCF boundary elements, can contact each other. Our findings suggest that activation of tissue-specific element(s)within such a self-interacting region is sufficient to influence all chromatin within the domain.
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Incorporating specific chromatin modifications and boundary elements at distant regulatory sites has created a more complete picture of the underlying regulation at the α-globin locus.
“Incorporating specific chromatin modifications and boundary elements at these distant regulatory sites has created a more complete picture of the underlying regulation at this locus (Brown et al., 2018; Hanssen et al., 2017; Oudelaar et al., 2017).”
From Unraveling Hematopoiesis through the Lens of Genomics (2020) · cites this paper as Brown et al., 2018
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A functional overlap between actively transcribed genes and chromatin boundary elementsPreprint
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FISH Going Meso-Scale: A Microscopic Search for Chromatin Domains
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Activation of alpha-globin transcription in primary mouse erythroid progenitors
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- Authors
- Brown, J. M., Roberts, N. A., Graham, B., Waithe, D., Lagerholm, C., Telenius, J. M., De Ornellas, S., Oudelaar, A. M., Scott, C., Szczerbal, I., Babbs, C., Kassouf, M. T., Hughes, J. R., Higgs, D. R., & Buckle, V. J.
- Affiliations
- University of Oxford (GB)
- MRC Weatherall Institute of Molecular Medicine (GB)
- Corresponding author
- Buckle, Veronica J.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-09-21
- Volume
- 9
- Issue
- 1
- Pages
- 3849-3849
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6155075
- OpenAlex
- W2782281541
- Cited by
- 72
- References
- 59
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 5 · 2023: 4 · 2022: 12 · 2021: 18 · 2020: 17 · 2019: 7 · 2018: 1
- FWCI
- 3.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (104924/Z/14/Z, G0902418, 104924, 106130/Z/14/Z, 106130)
- National Institute for Health and Care Research (131/030, 101/517)
- University of Oxford
- Medical Research Council (MR/K015777X/1, MC_UU_00016/4, MC_PC_15069, MR/N00969X/1, 106130/Z/14/Z, MC_UU_12025, #G0902418, MC_UU_00016/1, MC_UU_12009, MR/S005382/1, MC_UU_00008/6)
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council (BB/L01811X/1)
- 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
- enhancer-promoter interactions, 3D genome organization, CTCF, cohesin, loop domains, erythroid differentiation, cis-regulatory elements, transcription elongation
- MeSH terms
- Protein Domains, Animals, Chromatin, Regulatory Sequences, Nucleic Acid, In Situ Hybridization, Fluorescence, Erythroid Cells, Mice, alpha-Globins, Primary Cell Culture
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