Enhancer release and retargeting activates disease-susceptibility genes
Open accessAbstract
The functional engagement between an enhancer and its target promoter ensures precise gene transcription 1. Understanding the basis of promoter choice by enhancers has important implications for health and disease. Here we report that functional loss of a preferred promoter can release its partner enhancer to loop to and activate an alternative promoter (or alternative promoters) in the neighbourhood. We refer to this target-switching process as 'enhancer release and retargeting'. Genetic deletion, motif perturbation or mutation, and dCas9-mediated CTCF tethering reveal that promoter choice by an enhancer can be determined by the binding of CTCF at promoters, in a cohesin-dependent manner-consistent with a model of 'enhancer scanning' inside the contact domain. Promoter-associated CTCF shows a lower affinity than that at chromatin domain boundaries and often lacks a preferred motif orientation or a partnering CTCF at the cognate enhancer, suggesting properties distinct from boundary CTCF. Analyses of cancer mutations, data from the GTEx project and risk loci from genome-wide association studies, together with a focused CRISPR interference screen, reveal that enhancer release and retargeting represents an overlooked mechanism that underlies the activation of disease-susceptibility genes, as exemplified by a risk locus for Parkinson's disease (NUCKS1-RAB7L1) and three loci associated with cancer (CLPTM1L-TERT, ZCCHC7-PAX5 and PVT1-MYC).
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Deleting or inactivating the target promoter of a particular enhancer releases the enhancer to activate other local promoters.
“it was shown that deleting or inactivating the target promoter of a particular enhancer releases the enhancer to activate other local promoters [478].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [478]
Cites
Van der Auwera, G. A., Carneiro, M. O., Hartl, C., Poplin, R., del Angel, G., Levy‐Moonshine, A., Jordan, T., Shakir, K., Roazen, D., Thibault, J., et al. (2013) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi1110s43 · Cited by 6,687 · see citing works
Super-enhancers in the control of cell identity and disease
Hnisz, D., Abraham, B. J., Lee, T. I., Lau, A., Saint-André, V., Sigova, A. A., Hoke, H. A., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.09.053 · Cited by 3,662 · see citing works
Formation of chromosomal domains by loop extrusion
Fudenberg, G., Imakaev, M., Lu, C., Goloborodko, A., Abdennur, N., & Mirny, L. A. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.04.085 · Cited by 2,003 · see citing works
Cohesin Loss Eliminates All Loop Domains
Rao, S. S. P., Huang, S.-C., Glenn St Hilaire, B., Engreitz, J. M., Perez, E. M., Kieffer-Kwon, K.-R., Sanborn, A. L., Johnstone, S. E., Bascom, G. D., Bochkov, I. D., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.026 · Cited by 1,883 · see citing works
Nora, E. P., Goloborodko, A., Valton, A.-L., Gibcus, J. H., Uebersohn, A., Abdennur, N., Dekker, J., Mirny, L. A., & Bruneau, B. G. (2017) · Cell · doi:10.1016/j.cell.2017.05.004 · Cited by 1,709 · see citing works
Two independent modes of chromatin organization revealed by cohesin removal
Schwarzer, W., Abdennur, N., Goloborodko, A., Pekowska, A., Fudenberg, G., Loe-Mie, Y., Fonseca, N. A., Huber, W., Haering, C. H., Mirny, L., et al. (2017) · Nature · doi:10.1038/nature24281 · Cited by 1,196 · see citing works
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
CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function
Guo, Y., Xu, Q., Canzio, D., Shou, J., Li, J., Gorkin, D. U., Jung, I., Wu, H., Zhai, Y., Tang, Y., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.038 · Cited by 958 · see citing works
Self-citationUltrastructural 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
Genome-wide analysis of noncoding regulatory mutations in cancer
Weinhold, N., Jacobsen, A., Schultz, N., Sander, C., & Lee, W. (2014) · Nature Genetics · doi:10.1038/ng.3101 · Cited by 484 · see citing works
The structural basis for cohesin–CTCF-anchored loops
Li, Y., Haarhuis, J. H. I., Sedeño Cacciatore, Á., Oldenkamp, R., van Ruiten, M. S., Willems, L., Teunissen, H., Muir, K. W., de Wit, E., Rowland, B. D., et al. (2020) · Nature · doi:10.1038/s41586-019-1910-z · Cited by 459 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation
Yang, J. H., & Hansen, A. S. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00710-6 · Cited by 191 · see citing works
Transcriptional enhancers and their communication with gene promoters
Ray-Jones, H., & Spivakov, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03903-w · Cited by 81 · see citing works
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
Pericentromeric repetitive ncRNA regulates chromatin interaction and inflammatory gene expression
Miyata, K., & Takahashi, A. (2022) · Nucleus · doi:10.1080/19491034.2022.2034269 · Cited by 5 · see citing works
- Authors
- Oh, S., Shao, J., Mitra, J., Xiong, F., D’Antonio, M., Wang, R., Garcia-Bassets, I., Ma, Q., Zhu, X., Lee, J.-H., Nair, S. J., Yang, F., Ohgi, K., Frazer, K. A., Zhang, Z. D., Li, W., & Rosenfeld, M. G.
- Affiliations
- Howard Hughes Medical Institute (US)
- The University of Texas Health Science Center at Houston (US)
- Albert Einstein College of Medicine (US)
- University of California San Diego (US)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Li, Wenbo
- Rosenfeld, Michael G.
- ORCID
- Venue
- Nature
- Published
- 2021-05-26
- Volume
- 595
- Issue
- 7869
- Pages
- 735-740
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC11171441
- OpenAlex
- W3164418710
- Cited by
- 148
- References
- 11
- Citations by year
- 2026: 13 · 2025: 28 · 2024: 39 · 2023: 25 · 2022: 34 · 2021: 9
- FWCI
- 8.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (U01HL156059, R01HL150521, U01HL107442)
- National Human Genome Research Institute (R44HG008118, R41HG008118, R01HG008153)
- National Cancer Institute (R01CA184770, K22CA204468)
- National Institute of General Medical Sciences (R01GM136922, R21GM132778)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK105541, R01DK039949, DP3DK112155, R37DK039949, R01DK018477)
- National Institute of Neurological Disorders and Stroke (R01NS093066)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD008118)
- 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 › Genetics › Genetic Associations and Epidemiology
- Keywords
- enhancer-promoter interactions, CTCF, cohesin, alternative promoters, susceptibility genes, cancer risk loci, Parkinson's disease, CRISPR interference screen, enhancer looping, chromatin organization
- MeSH terms
- CCCTC-Binding Factor, Cohesins, Cells, Cultured, Chromatin, Chromosomal Proteins, Non-Histone, Enhancer Elements, Genetic, Humans, Neoplasms, Oncogenes, Parkinson Disease, Promoter Regions, Genetic, Gene Expression Regulation, Neoplastic, Gene Deletion, Cell Cycle Proteins, Genetic Predisposition to Disease, Genome-Wide Association Study, Neural Stem Cells, MCF-7 Cells, CRISPR-Cas Systems
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 ›
Are you an author, or do you see a problem with this page? Request a review
