Dynamics of the 4D Genome during in Vivo Lineage Specification and Differentiation
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Abstract
Mammalian gene expression patterns are controlled by regulatory elements, which interact within topologically associating domains (TADs). The relationship between activation of regulatory elements, formation of structural chromatin interactions and gene expression during development is unclear. Here, we present Tiled-C, a low-input chromosome conformation capture (3C) technique. We use this approach to study chromatin architecture at high spatial and temporal resolution through in vivo mouse erythroid differentiation. Integrated analysis of chromatin accessibility and single-cell expression data shows that regulatory elements gradually become accessible within pre-existing TADs during early differentiation. This is followed by structural re-organization within the TAD and formation of specific contacts between enhancers and promoters. Our high-resolution data show that these enhancer-promoter interactions are not established prior to gene expression, but formed gradually during differentiation, concomitant with progressive upregulation of gene activity. Together, these results provide new insight into the close, interdependent relationship between chromatin architecture and gene regulation during development.
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Tiled-C was conducted as previously described.
“Tiled-C, a high-resolution Chromosome Conformation Capture (3C) method that produces contact matrices of selected regions of interest was conducted as previously described.41”
From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [41]
In mammalian differentiation models, extensive remodelling of enhancer-promoter contacts is typically observed consistently with enhancer activation.
“In mammalian differentiation models, in contrast, extensive remodelling of enhancer–promoter contacts is typically observed consistently with enhancer activation [141, 394–397].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [396]
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- Authors
- 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., Telenius, J. M., Brown, T., Buckle, V. J., Socolovsky, M., Higgs, D. R., & Hughes, J. R.
- Affiliations
- University of Oxford (GB)
- University of Massachusetts Chan Medical School (US)
- Suez University (EG)
- Corresponding author
- Higgs, Douglas R.
- Hughes, Jim R.
- ORCID
- Venue
- Nature Communications
- Published
- 2020-06-01
- Volume
- 11
- Issue
- 1
- Pages
- 2722-2722
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7264236
- OpenAlex
- W3030892594
- Cited by
- 119
- References
- 61
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 19 · 2023: 20 · 2022: 17 · 2021: 20 · 2020: 14
- FWCI
- 5.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- RCUK | Medical Research Council
- Wellcome Trust
- 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
- topologically associating domains, chromatin structure, enhancer-promoter interactions, erythroid differentiation, lineage specification, chromatin accessibility, chromosome conformation capture, regulatory elements, single-cell gene expression, mouse embryo
- MeSH terms
- Mouse Embryonic Stem Cells, Animals, Cell Differentiation, Cells, Cultured, Chromatin, Enhancer Elements, Genetic, Female, Hematopoietic Stem Cells, Mice, Inbred C57BL, Promoter Regions, Genetic, Stem Cells, Genome, Gene Expression Regulation, Developmental, Gene Expression Profiling, Chromosomes, Mammalian, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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