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Cited by 120Genomics and Chromatin DynamicsDevelopmental Biology and Gene RegulationEpigenetics and DNA Methylation

Enhancer-promoter interactions can bypass CTCF-mediated boundaries and contribute to phenotypic robustness

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Chakraborty, Shreeta, Kopitchinski, Nina, Zuo, Zhenyu, Eraso, Ariel, Awasthi, Parirokh, Chari, Raj, Mitra, Apratim, Tobias, Ian C. +5 more·2023·Nature Genetics
DOI 10.1038/s41588-022-01295-6PMC PMC10758292

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Abstract

How enhancers activate their distal target promoters remains incompletely understood. Here we dissect how CTCF-mediated loops facilitate and restrict such regulatory interactions. Using an allelic series of mouse mutants, we show that CTCF is neither required for the interaction of the Sox2 gene with distal enhancers, nor for its expression. Insertion of various combinations of CTCF motifs, between Sox2 and its distal enhancers, generated boundaries with varying degrees of insulation that directly correlated with reduced transcriptional output. However, in both epiblast and neural tissues, enhancer contacts and transcriptional induction could not be fully abolished, and insertions failed to disrupt implantation and neurogenesis. In contrast, Sox2 expression was undetectable in the anterior foregut of mutants carrying the strongest boundaries, and these animals fully phenocopied loss of SOX2 in this tissue. We propose that enhancer clusters with a high density of regulatory activity can better overcome physical barriers to maintain faithful gene expression and phenotypic robustness.

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Authors
Chakraborty, S., Kopitchinski, N., Zuo, Z., Eraso, A., Awasthi, P., Chari, R., Mitra, A., Tobias, I. C., Moorthy, S. D., Dale, R. K., Mitchell, J. A., Petros, T. J., & Rocha, P. P.
Affiliations
  • National Institutes of Health (US)
  • Frederick National Laboratory for Cancer Research (US)
  • University of Toronto (CA)
Corresponding author
Rocha, Pedro P.
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2023-01-30
Volume
55
Issue
2
Pages
280-290
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/s41588-022-01295-6
PMC
PMC10758292
OpenAlex
W4318486619
Cited by
120
References
30
Citations by year
2026: 29 · 2025: 24 · 2024: 35 · 2023: 22 · 2022: 10
FWCI
9.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Genetics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD008975, HD008986, HD008962)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (HHSN261201500003I)
  • Gouvernement du Canada | Canadian Institutes of Health Research (FRN 153186)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
enhancer-promoter interactions, CTCF, chromatin looping, SOX2, distal enhancers, phenotypic robustness, epiblast, neural development, gene expression regulation, mouse mutants
MeSH terms
CCCTC-Binding Factor, Animals, Chromatin, Enhancer Elements, Genetic, Promoter Regions, Genetic, Mice

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