CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2
Abstract
It is thought that the H19 imprinting control region (ICR) directs the silencing of the maternally inherited Igf2 allele through a CTCF-dependent chromatin insulator. The ICR has been shown to interact physically with a silencer region in Igf2, differentially methylated region (DMR)1, but the role of CTCF in this chromatin loop and whether it restricts the physical access of distal enhancers to Igf2 is not known. We performed systematic chromosome conformation capture analyses in the Igf2/H19 region over >160 kb, identifying sequences that interact physically with the distal enhancers and the ICR. We found that, on the paternal chromosome, enhancers interact with the Igf2 promoters but that, on the maternal allele, this is prevented by CTCF binding within the H19 ICR. CTCF binding in the maternal ICR regulates its interaction with matrix attachment region (MAR)3 and DMR1 at Igf2, thus forming a tight loop around the maternal Igf2 locus, which may contribute to its silencing. Mutation of CTCF binding sites in the H19 ICR leads to loss of CTCF binding and de novo methylation of a CTCF target site within Igf2 DMR1, showing that CTCF can coordinate regional epigenetic marks. This systematic chromosome conformation capture analysis of an imprinting cluster reveals that CTCF has a critical role in the epigenetic regulation of higher-order chromatin structure and gene silencing over considerable distances in the genome.
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Parent-of-origin specific gene activity at the imprinted IGF2/H19 locus is controlled by allele-specific CTCF-CTCF interactions that constrain enhancer-gene contacts in a DNA methylation-dependent manner.
“Parent-of-origin specific gene activity at the imprinted IGF2/H19 locus is controlled by allele-specific CTCF-CTCF interactions that constrain enhancer-gene contacts in a DNA methylation-dependent manner (Figure 6A) (Kurukuti et al., 2006; Murrell et al., 2004).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Kurukuti et al., 2006
A larger insulated neighborhood is formed on the paternal allele to allow an enhancer-promoter interaction that activates the IGF2 gene.
“A larger insulated neighborhood is formed on the paternal allele to allow an enhancer-promoter interaction that activates the IGF2 gene.”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Kurukuti et al., 2006
An insulated neighborhood on the maternal allele allows an enhancer-promoter interaction that activates the H19 gene but not the IGF2 gene, which is excluded from the neighborhood.
“An insulated neighborhood on the maternal allele allows an enhancer-promoter interaction that activates the H19 gene but not the IGF2 gene, which is excluded from the neighborhood.”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Kurukuti et al., 2006
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- Authors
- Kurukuti, S., Tiwari, V. K., Tavoosidana, G., Pugacheva, E., Murrell, A., Zhao, Z., Lobanenkov, V., Reik, W., & Ohlsson, R.
- Affiliations
- Uppsala University (SE)
- National Institutes of Health (US)
- University of Cambridge (GB)
- Babraham Institute (GB)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-07-11
- Volume
- 103
- Issue
- 28
- Pages
- 10684-10689
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2152968621
- Cited by
- 511
- References
- 43
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 8 · 2023: 15 · 2022: 13 · 2021: 9 · 2020: 11 · 2019: 9 · 2018: 17 · 2017: 21 · 2016: 26 · 2015: 21 · 2014: 27 · 2013: 26 · 2012: 54
- FWCI
- 18.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (Queen's University Belfast) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- CTCF, insulin-like growth factor II, genomic imprinting, chromatin looping, enhancer-promoter interactions, chromatin insulators, matrix attachment regions, DNA methylation, epigenetic regulation, higher-order chromatin structure, gene silencing, maternal allele
- MeSH terms
- CCCTC-Binding Factor, Animals, DNA-Binding Proteins, Enhancer Elements, Genetic, Female, Heterochromatin, Insulin-Like Growth Factor II, Male, Protein Binding, Protein Conformation, Proteins, Repressor Proteins, Genomic Imprinting, Gene Silencing, RNA, Untranslated, Epigenesis, Genetic, Mice, RNA, Long Noncoding
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