Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive
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In mammals, a subset of genes inherit gametic marks that establish parent of origin-dependent expression patterns in the soma ([1] and references therein). The currently most extensively studied examples of this phenomenon, termed genomic imprinting, are the physically linked Igf2 (insulin-like growth factor II) and H19 genes, which are expressed mono-allelically from opposite parental alleles [1] [2]. The repressed status of the maternal Igf2 allele is due to cis elements that prevent the H19 enhancers [3] from accessing the Igf2 promoters on the maternal chromosome [4] [5]. A differentially methylated domain (DMD) in the 5' flank of H19 is maintained paternally methylated and maternally unmethylated [6] [7]. We show here by gel-shift and chromatin immunopurification analyses that binding of the highly conserved multivalent factor CTCF ([8] [9] and references therein) to the H19 DMD is methylation-sensitive and parent of origin-dependent. Selectively mutating CTCF-contacting nucleotides, which were identified by methylation interference within the extended binding sites initially revealed by nuclease footprinting, abrogated the H19 DMD enhancer-blocking property. These observations suggest that molecular mechanisms of genomic imprinting may use an unusual ability of CTCF to interact with a diverse spectrum of variant target sites, some of which include CpGs that are responsible for methylation-sensitive CTCF binding in vitro and in vivo.
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CTCF binding has an insulating capacity, effectively blocking signals between enhancers and their target genes in the β-globin and H19/Igf2 loci.
“More unusually, it emerged that CTCF binding has an insulating capacity, effectively blocking signals between enhancers and their target genes in the β-globin and H19/Igf2 loci [323–326].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [326]
DNA methylation abrogates CTCF DNA binding.
“DNA methylation abrogates CTCF DNA binding (Bell and Felsenfeld, 2000; Hark et al., 2000; Kanduri et al., 2000; Szabo et al., 2000).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Kanduri et al., 2000
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- Authors
- Kanduri, C., Pant, V., Loukinov, D., Pugacheva, E., Qi, C.-F., Wolffe, A., Ohlsson, R., & Lobanenkov, V. V.
- Affiliations
- Uppsala University (SE)
- National Institutes of Health (US)
- Sangamo BioSciences (United States) (US)
- Corresponding author
- Ohlsson, Rolf
- Lobanenkov, Victor V.
- ORCID
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2000-07
- Volume
- 10
- Issue
- 14
- Pages
- 853-856
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2074906225
- Cited by
- 444
- References
- 12
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 9 · 2022: 5 · 2021: 7 · 2020: 9 · 2019: 5 · 2018: 9 · 2017: 11 · 2016: 9 · 2015: 13 · 2014: 13 · 2013: 16 · 2012: 22
- FWCI
- 17.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- CTCF, genomic imprinting, H19, differentially methylated regions, insulin-like growth factor II, DNA methylation, enhancer blocking, chromatin insulators, CpG sites, monoallelic expression, CTCF binding sites
- MeSH terms
- CCCTC-Binding Factor, Animals, Base Sequence, Binding Sites, DNA, DNA-Binding Proteins, Enhancer Elements, Genetic, Female, Insulin-Like Growth Factor II, Male, Molecular Sequence Data, Muscle Proteins, Protein Binding, Repressor Proteins, Transcription Factors, Zinc Fingers, DNA Methylation, RNA, Untranslated, Mice, RNA, Long Noncoding
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