A genome-wide nucleosome-resolution map of promoter-centered interactions in human cells corroborates the enhancer-promoter looping model
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Abstract The enhancer-promoter looping model, in which enhancers activate their target genes via physical contact, has long dominated the field of gene regulation. However, the ubiquity of this model has been questioned due to evidence of alternative mechanisms and the lack of its systematic validation, primarily owing to the absence of suitable experimental techniques. In this study, we present a new MNase-based proximity ligation method called MChIP-C, allowing for the measurement of protein-mediated chromatin interactions at single-nucleosome resolution on a genome-wide scale. By applying MChIP-C to study H3K4me3 promoter-centered interactions in K562 cells, we found that it had greatly improved resolution and sensitivity compared to restriction endonuclease-based C-methods. This allowed us to identify EP300 histone acetyltransferase and the SWI/SNF remodeling complex as potential candidates for establishing and/or maintaining enhancer-promoter interactions. Finally, leveraging data from published CRISPRi screens, we found that most functionally-verified enhancers do physically interact with their cognate promoters, supporting the enhancer-promoter looping model.
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In K562 cells, more than 65% of functionally confirmed enhancer-promoter pairs are characterized by the formation of enhancer-promoter loops.
“A recent analysis of enhancer-promoter loops using the micro-C technique demonstrated that in K562 cells, more than 65% of functionally confirmed enhancer-promoter pairs are characterized by the formation of enhancer-promoter loops [90].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [90]
The Results report that 61.5% (216/351) of functionally verified enhancer–promoter pairs in K562 had spatial interactions detected, supporting the claim that a majority interact—but not the stated figure of more than 65%. The Abstract and Results identify the method as MChIP-C, not Micro-C. (LLM, conf=0.91)
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Long-range enhancer–promoter contacts in gene expression control
Schoenfelder, S., & Fraser, P. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0128-0 · Cited by 1,102 · see citing works
BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis
Canver, M. C., Smith, E. C., Sher, F., Pinello, L., Sanjana, N. E., Shalem, O., Chen, D. D., Schupp, P. G., Vinjamur, D. S., Garcia, S. P., et al. (2015) · Nature · doi:10.1038/nature15521 · Cited by 886 · see citing works
Systematic mapping of functional enhancer–promoter connections with CRISPR interference
Fulco, C. P., Munschauer, M., Anyoha, R., Munson, G., Grossman, S. R., Perez, E. M., Kane, M., Cleary, B., Lander, E. S., & Engreitz, J. M. (2016) · Science · doi:10.1126/science.aag2445 · Cited by 643 · see citing works
Ultrastructural Details of Mammalian Chromosome Architecture
Krietenstein, N., Abraham, S., Venev, S. V., Abdennur, N., Gibcus, J., Hsieh, T.-H. S., Parsi, K. M., Yang, L., Maehr, R., Mirny, L. A., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.03.003 · Cited by 622 · see citing works
Hughes, J. R., Roberts, N., McGowan, S., Hay, D., Giannoulatou, E., Lynch, M., De Gobbi, M., Taylor, S., Gibbons, R., & Higgs, D. R. (2014) · Nature Genetics · doi:10.1038/ng.2871 · Cited by 461 · see citing works
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Mapping of long-range chromatin interactions by proximity ligation-assisted ChIP-seq
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Multiplexed analysis of chromosome conformation at vastly improved sensitivity
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Enhancer Function in the 3D Genome
Razin, S. V., Ulianov, S. V., & Iarovaia, O. V. (2023) · Genes · doi:10.3390/genes14061277 · Cited by 15 · see citing works
Self-citation
- Authors
- Golov, A. K., Gavrilov, A. A., Kaplan, N., & Razin, S. V.
- Affiliations
- Russian Academy of Sciences (RU)
- Technion – Israel Institute of Technology (IL)
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2023-12-18
- ISSN
- 2050-084X (ISSN-L)
- OpenAlex
- W4389921438
- Cited by
- 4
- References
- 10
- Citations by year
- 2025: 1 · 2024: 3
- Type
- posted content
- Language
- en
- Open access
- gold
- doi.org
- Locations
- eLife (acceptedVersion, cc-by)
- Funders
- Technion - Israel Institute of Technology, RBNI - Russell Berrie Nanotechnology Institute
- Russian Science Foundation (21-64-00001)
- 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
- enhancer-promoter looping, enhancer-promoter interactions, H3K4me3, chromatin interactions, EP300, K562 cells, CRISPRi screen, gene expression regulation, chromatin looping
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