CpG methylation regulates the Igf2/H19 insulator

Holmgren, Claes; Kanduri, Chandrasekhar; Dell, Ghislaine; Ward, Andrew; Mukhopadhya, Rituparna; Kanduri, Meena; Lobanenkov, Victor; Ohlsson, Rolf

doi:10.1016/s0960-9822(01)00314-1

Cited by 78 publications

(49 citation statements)

References 10 publications

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“…The silenced maternal Igf2 allele requires the continuous presence of the H19 imprinting control region (ICR) 1 (3), which has been proposed to function as a chromatin insulator by default (4 -7). In line with this supposition, the H19 ICR has no insulator function when methylated (8).…”

supporting

confidence: 58%

Multiple cis Elements within theIgf2/H19 Insulator Domain Organize a Distance-dependent Silencer

Ginjala

Holmgren

Ullerås

et al. 2002

Journal of Biological Chemistry

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The 5-flank of the H19 gene harbors a differentially methylated imprinting control region that represses the maternally derived Igf2 and paternally derived H19 alleles. Here we show that the H19 imprinting control region (ICR) is a potent silencer when positioned in a promoter-proximal position. The silencing effect is not alleviated by trichostatin A treatment, suggesting that it does not involve histone deacetylase functions. When the H19 ICR is separated from the promoter by more than 1.2 ؎ 0.3 kb, however, trichostatin A stimulates promoter activity 10-fold. Deletion analyses revealed that the silencing feature extended throughout the ICR segment. Finally, chromatin immunopurification analyses revealed that the H19 ICR prevented trichostatin A-dependent reacetylation of histones in the promoter region in a proximal but not in a distal position. We argue that these features are likely to be side effects of the H19 ICR, rather than explaining the mechanism of silencing of the paternal H19 allele. We issue a cautionary note, therefore, that the interpretation of insulator/ silencer data could be erroneous should the distance issue not be taken into consideration.

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supporting

confidence: 58%

Multiple cis Elements within theIgf2/H19 Insulator Domain Organize a Distance-dependent Silencer

Ginjala

Holmgren

Ullerås

et al. 2002

Journal of Biological Chemistry

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“…IGF2 expression is controlled by genomic imprinting where the paternal allele is active in transcription while the maternal allele is silent due to a lack of methylation at the ICR (imprinting control region) (Giannoukakis et al, 1993;Ogawa et al, 1993;Ohlsson et al, 1993;Rainier et al, 1993). An 11-zincfinger transcription factor CTCF has been linked with binding to that region and is shown to be critical for maintaining IGF2 imprinting (Hark et al, 2000;Holmgren et al, 2001).…”

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confidence: 99%

IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1

Sun¹,

Gao²,

Liu³

et al. 2005

Oncogene

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Synovial sarcoma is an aggressive soft tissue tumor characterized by a specific chromosomal translocation between chromosome 18 and X. This translocation can generate a fusion transcript encoding SYT-SSX1, a transforming oncoprotein. We present evidence that SYT-SSX1 induces insulin-like growth factor II expression in fibroblast cells. SYT-SSX2, a fusion also frequently found in synovial sarcoma, is necessary for maintaining Igf2 expression in the synovial sarcoma cell line, and the increased IGF2 synthesis protects cells from anoikis and is required for tumor formation in vivo. We also found a loss of imprinting (LOI) for Igf2 in a limited number of primary synovial sarcomas despite demethylation of CpG dinucleotides critical for maintaining imprinting. These findings suggest that inhibition of the IGF2/IGF1-R signaling pathway may represent a significant therapeutic modality for treating synovial sarcoma.

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“…The deletion of this ICR results in biallelic expression of both Igf2 and H19, demonstrating a role of the ICR to repress the maternal Igf2 allele, which is located Ͼ80 kb away (12). The mechanism underlying this function has been proposed to involve a CTCF-dependent chromatin insulator located within the ICR (13)(14)(15)(16), which is continuously required for Igf2 repression in somatic cells (17). However, the Igf2 gene itself also contains differentially methylated regions (DMRs), with DMR1 being a methylation-sensitive silencer (18,19) and DMR2 being a methylation sensitive activator (20).…”

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confidence: 99%

CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2

Kurukuti

Tiwari²,

Tavoosidana³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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It is thought that the H19 imprinting control region (ICR) directs the silencing of the maternally inherited Igf2 allele through a CTCFdependent 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 Igf2͞H19 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.genomic imprinting ͉ insulators ͉ chromosome biology A variety of control elements, such as enhancers, silencers, and chromatin insulators, are thought to establish and maintain domains of gene expression or repression in the genome. Insulators, for example, are needed to keep genes in silent domains, away from the influence of neighboring enhancers. The prototypical insulator from the chicken ␤-globin locus contains binding sites for the 11-zinc-finger protein CTCF, and binding of CTCF is necessary for insulator function, not only in the chicken but also in many mammalian insulators (1-4). How CTCF confers chromatin insulation is not clear, but recent work shows that DNA-bound CTCF molecules can dimerize in a binding site-specific fashion (5) and that CTCF binds nucleophosmin and may be tethered to the nuclear matrix (6). CTCF emerges, therefore, as a potential mediator of long-range interactions that are involved in establishing repressed domains.Regional coordination of gene expression and repression is found in many imprinted gene clusters in the mammalian genome and is regulated by imprinting centers or imprinting control regions (ICRs) (7-10). A well characterized cluster is that containing the paternally expressed Igf2 and maternally expressed H19. Both genes share enhancers, and the ICR is located in the 5Ј flank of the H19 gene (11). The deletion of this ICR results in biallelic expression of both Igf2 and H19, demonstrating a role of the ICR to repress the maternal Igf2 allele, which is located Ͼ80 kb away (12). The mechanism underlying this function has been proposed to involve a CTCF-dependent...

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CpG methylation regulates the Igf2/H19 insulator

Cited by 78 publications

References 10 publications

Multiple cis Elements within theIgf2/H19 Insulator Domain Organize a Distance-dependent Silencer

Multiple cis Elements within theIgf2/H19 Insulator Domain Organize a Distance-dependent Silencer

IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1

CTCF binding at the H19 imprinting control region mediates maternally inherited higher-order chromatin conformation to restrict enhancer access to Igf2

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