The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements
Open accessAbstract
The mammalian genome harbors up to one million regulatory elements often located at great distances from their target genes. Long-range elements control genes through physical contact with promoters and can be recognized by the presence of specific histone modifications and transcription factor binding. Linking regulatory elements to specific promoters genome-wide is currently impeded by the limited resolution of high-throughput chromatin interaction assays. Here we apply a sequence capture approach to enrich Hi-C libraries for >22,000 annotated mouse promoters to identify statistically significant, long-range interactions at restriction fragment resolution, assigning long-range interacting elements to their target genes genome-wide in embryonic stem cells and fetal liver cells. The distal sites contacting active genes are enriched in active histone modifications and transcription factor occupancy, whereas inactive genes contact distal sites with repressive histone marks, demonstrating the regulatory potential of the distal elements identified. Furthermore, we find that coregulated genes cluster nonrandomly in spatial interaction networks correlated with their biological function and expression level. Interestingly, we find the strongest gene clustering in ES cells between transcription factor genes that control key developmental processes in embryogenesis. The results provide the first genome-wide catalog linking gene promoters to their long-range interacting elements and highlight the complex spatial regulatory circuitry controlling mammalian gene expression.
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A similar network of contacts is detectable between active promoters of multiple histone genes in many mammalian cell types.
“A similar network of contacts is also detectable between the active promoters of multiple histone genes in many mammalian cell types [243, 279, 471, 492].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [279]
In Results > Promoter capture Hi-C (page unavailable), the paper reports contact enrichment between the Hist1h4h and Hist1h2ai loci in mouse embryonic stem cells and fetal liver cells. Results > Promoter–promoter 3D interaction networks reports preferential contacts among promoters more broadly. These passages do not establish a network specifically among active histone-gene promoters in many mammalian cell types. (LLM, conf=0.84)
Experimental — accuracy not yet measuredEnhancers vastly outnumber promoters in human and mouse genomes, and promoters often contact more than one enhancer in the same cell type.
“Enhancers vastly outnumber promoters in human and mouse genomes [131], and consistently promoters often contact more than one enhancer in the same cell type [141, 243, 278, 279].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [279]
The number of enhancers correlates with the expression level of a gene across cell types.
“the number of enhancers correlates with the expression level of a gene across cell types [243, 278, 279, 349].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [279]
TADs correspond to functional regulatory domains by primarily restricting contact between enhancers and promoters to occur within the same TAD.
“A large body of evidence suggests that TADs correspond to functional regulatory domains by primarily restricting contact between enhancers and promoters to occur within the same TAD3,21–25”
From Recent evidence that TADs and chromatin loops are dynamic structures (2018) · cites this paper as [23]
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Self-citation
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- Authors
- Schoenfelder, S., Furlan-Magaril, M., Mifsud, B., Tavares-Cadete, F., Sugar, R., Javierre, B.-M., Nagano, T., Katsman, Y., Sakthidevi, M., Wingett, S. W., Dimitrova, E., Dimond, A., Edelman, L. B., Elderkin, S., Tabbada, K., Darbo, E., Andrews, S., Herman, B., Higgs, A., LeProust, E., Osborne, C. S., Mitchell, J. A., Luscombe, N. M., & Fraser, P.
- Affiliations
- Babraham Institute (GB)
- Cancer Research UK (GB)
- European Bioinformatics Institute (GB)
- University of Toronto (CA)
- Agilent Technologies (United States) (US)
- Okinawa Institute of Science and Technology Graduate University (JP)
- Corresponding author
- Luscombe, Nicholas M.
- Fraser, Peter
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2015-03-09
- Volume
- 25
- Issue
- 4
- Pages
- 582-597
- ISSN
- 1088-9051 (ISSN-L)
- 1549-5469
- PMC
- PMC4381529
- OpenAlex
- W2152791321
- Cited by
- 460
- References
- 80
- Citations by year
- 2026: 9 · 2025: 24 · 2024: 35 · 2023: 36 · 2022: 63 · 2021: 56 · 2020: 48 · 2019: 45 · 2018: 39 · 2017: 42 · 2016: 36 · 2015: 27
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Biotechnology and Biological Science Research Council, UK
- Medical Research Council
- Canadian Institutes of Health Research
- Canada Foundation for Innovation
- Ontario Ministry of Research and Innovation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- long-range chromatin interactions, enhancer-promoter interactions, 3D genome organization, Hi-C, histone modifications, transcription factor binding, embryonic stem cells, fetal liver cells, gene co-regulation, spatial interaction networks, transcriptional regulation, mouse genome
- MeSH terms
- Animals, Binding Sites, Chromatin, Enhancer Elements, Genetic, Histones, Liver, Mice, Inbred C57BL, Promoter Regions, Genetic, Transcription Factors, Gene Expression Regulation, Developmental, Epigenesis, Genetic, Mice, Embryonic Stem Cells
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.
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