Insulator and silencer sequences in the imprinted region of human chromosome 11p15.5

Du, Minjie; Beatty, Linda G.; Zhou, Wenjing; Lew, J.; Schoenherr, Christopher J.; Weksberg, Rosanna; Sadowski, Paul D.

doi:10.1093/hmg/ddg194

Cited by 57 publications

(57 citation statements)

References 62 publications

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“…It has been reported that DMR-LIT1 are an orientation-independent silencer (Du et al, 2003;ManciniDiNardo et al, 2003;Thakur et al, 2003). Thakur et al (2003) proposed that a repressive chromatin structure established at DMR-LIT1 might propagate bidirectionally along the DNA to inactivate neighboring genes.…”

Section: Discussionmentioning

confidence: 99%

“…H3K9 methylation was, however, barely detectable at CDKN1C promoter in the cancer cell lines and undetectable in cells with normal MI, suggesting that H3K9 methylation is not involved in CDKN1C repression on the paternal epigenotype chromosome. Since the human CDKN1C sequence was also reported to be an orientation-independent silencer (Du et al, 2003) and was not differentially methylated, CDKN1C may be synergistically repressed by the imprinting suppression and its own silencing activity on the paternal allele. In addition, methylated DMR-LIT1 on the maternal allele may function as a repressor of the CDKN1C silencer, leading to maternal expression.…”

Section: Discussionmentioning

confidence: 99%

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Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

Soejima¹,

Nakagawachi²,

Zhao³

et al. 2004

Oncogene

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The putative tumor suppressor CDKN1C is an imprinted gene at 11p15.5, a well-known imprinted region often deleted in tumors. The absence of somatic mutations and the frequent diminished expression in tumors would suggest that CDKN1C expression is regulated epigenetically. It has been, however, controversial whether the diminution is caused by imprinting disruption of the CDKN1C/LIT1 domain or by promoter hypermethylation of CDKN1C itself. To clarify this, we investigated the CpG methylation index of the CDKN1C promoter and the differentially methylated region of the LIT1 CpG island (differentially methylated region (DMR)-LIT1), an imprinting control region of the domain, and CDKN1C expression in esophageal cancer cell lines. CDKN1C expression was diminished in 10 of 17 lines and statistically correlated with the loss of methylation at DMR-LIT1 in all but three. However, there was no statistical correlation between CDKN1C promoter MI and CDKN1C expression. Furthermore, loss of CpG methylation was associated with loss of histone H3 lysine 9 (H3K9) methylation at DMR-LIT1. Histone modifications at CDKN1C promoter were not correlated with CDKN1C expression. The data suggested that the diminished CDKN1C expression is associated with the loss of methylation of CpG and H3K9 at DMR-LIT1, not by its own promoter CpG methylation, and is involved in esophageal cancer, implying that DMR-LIT1 epigenetically regulates CDKN1C expression not through histone modifications at CDKN1C promoter, but through that of DMR-LIT1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

Soejima¹,

Nakagawachi²,

Zhao³

et al. 2004

Oncogene

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confidence: 99%

“…Consistent with its function as an ICR, targeted deletions of sequence spanning the DMD result in loss of both Igf2 and H19 imprinted expression (19,43,51,52). To date, the insulator model of imprinting control remains unique to the H19/ Igf2 locus, although other ICRs are expected to bind CTCF and/or exhibit insulator activity in vitro, including the KvDMR1 at the Kcnq1 locus (8,11,14).While targeted deletions of the DMD have suggested that at least three of the four CTCF binding sites are necessary for Igf2 and H19 imprinting (10, 51), DMD replacement alleles have been essential in validating the role of CTCF in regulating DMD function. The DMD replacement alleles with mutations that block CTCF binding perturb imprinting exclusively when maternally inherited: Igf2 becomes biallelically expressed due to loss of CTCF-dependent DMD insulator activity (31,41,47).…”

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confidence: 99%

Developmental Profile of H19 Differentially Methylated Domain (DMD) Deletion Alleles Reveals Multiple Roles of the DMD in Regulating Allelic Expression and DNA Methylation at the Imprinted H19/Igf2 Locus

Thorvaldsen

Fedoriw

Nguyen

et al. 2006

Molecular and Cellular Biology

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The differentially methylated domain (DMD) of the mouse H19 gene is a methylation-sensitive insulator that blocks access of the Igf2 gene to shared enhancers on the maternal allele and inactivates H19 expression on the methylated paternal allele. By analyzing H19 DMD deletion alleles H19 ⌬DMD and H19 ⌬3.8kb-5H19 in pre-and postimplantation embryos, we show that the DMD exhibits positive transcriptional activity and is required for H19 expression in blastocysts and full activation of H19 during subsequent development. We also show that the DMD is required to establish Igf2 imprinting by blocking access to shared enhancers when Igf2 monoallelic expression is initiated in postimplantation embryos and that the single remaining CTCF site of the H19 ⌬DMD allele is unable to provide this function. Furthermore, our data demonstrate that sequence outside of the DMD can attract some paternal-allele-specific CpG methylation 5 of H19 in preimplantation embryos, although this methylation is not maintained during postimplantation in the absence of the DMD. Finally, we report a conditional allele floxing the 1.6-kb sequence deleted from the H19 ⌬DMD allele and demonstrate that the DMD is required to maintain repression of the maternal Igf2 allele and the full activity of the paternal Igf2 allele in neonatal liver.Genomic imprinting is a mammalian epigenetic phenomenon whereby the parental origin of a gene determines whether or not it will be expressed. Over 75 imprinted genes have been identified, many of which are noncoding RNAs that are hypothesized to control the expression of linked protein coding genes that are also imprinted (59). Imprinted genes tend to be clustered with other imprinted genes with which they sometimes share common tissue-specific expression patterns. While an understanding of the mechanism by which imprinting occurs is dependent upon the identification of cis-acting control elements, few elements have been thus far characterized. As such, tissue-specific enhancers have only been elucidated for the imprinted locus encompassing the oppositely imprinted H19 and Igf2 genes. In addition to shared enhancers, most imprinting clusters harbor an imprinting control region (ICR) that governs the imprinting of the entire cluster.ICRs are associated with sequences that carry imprinting marks (IMs), which are epigenetic modifications that distinguish the parental alleles. By definition, IMs are established in the germ line and maintained throughout development. To date, allele-specific methylation of CpG dinucleotides qualifies as an IM. At the H19/Igf2 locus, the ICR is associated with the paternally methylated 2-kb differentially methylated domain (DMD) upstream of H19 (54, 55). The DMD, which is located 2 kb 5Ј of H19 and approximately 90 kb 3Ј of Igf2, is a CTCFdependent, methylation-sensitive insulator that blocks enhancer-driven Igf2 expression on the hypomethylated maternal allele and functions as a silencing element to repress H19 expression on the hypermethylated paternal allele (3,15,20,59). Consistent with...

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“…Hence the presence of these specific repeats appears to be a hallmark of the IC2 region. Among the conserved motifs, we also found one copy of motif A2 in the chicken CpG island.In addition, we searched for consensus sequences of CTCF and YY1 binding sites (Bell and Felsenfeld 2000;Du et al 2003;Kim et al 2003) and other specific motifs of unknown function which were discussed as potential signatures of imprinting centers in the literature (Wang et al 2004). Based on consensus sequences, none of these motifs was found to be conserved in the putative mammalian IC2 CpG islands.…”

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confidence: 99%

Evolution of the Beckwith-Wiedemann syndrome region in vertebrates

Paulsen¹,

Khare²,

Burgard³

et al. 2004

Genome Res.

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In the animal kingdom, genomic imprinting appears to be restricted to mammals. It remains an open question how structural features for imprinting evolved in mammalian genomes. The clustering of genes around imprinting control centers (ICs) is regarded as a hallmark for the coordinated imprinted regulation. Hence imprinted clusters might be structurally distinct between mammals and nonimprinted vertebrates. To address this question we compared the organization of the Beckwith Wiedemann syndrome (BWS) gene cluster in mammals, chicken, Fugu (pufferfish), and zebrafish. Our analysis shows that gene synteny is apparently well conserved between mammals and birds, and is detectable but less pronounced in fish. Hence, clustering apparently evolved during vertebrate radiation and involved two major duplication events that took place before the separation of the fish and mammalian lineages. A cross-species analysis of imprinting center regions showed that some structural features can already be recognized in nonimprinted amniotes in one of the imprinting centers (IC2). In contrast, the imprinting center IC1 is absent in chicken. This suggests a progressive and stepwise evolution of imprinting control elements. In line with that, imprinting centers in mammals apparently exhibit a high degree of structural and sequence variation despite conserved epigenetic marking.[Supplemental material is available online at www.genome.org.]Genomic imprinting describes mono-allelic gene expression in diploid organisms depending on the parental origin of the allele. Thus far, imprinting effects on gene expression have been observed mainly in mammalian species and in flowering plants (Grossniklaus et al. 2001;Reik and Walter 2001; http:// cancer.otago.ac.nz/IGC/Web/home.html, http://www.mgu.har. mrc.ac.uk/imprinting/imprinting.html). In analyzed organisms only a small number of genes appears to be affected, whereas the majority is biallelically expressed. As imprinting effects are absent or marginal in other clades, it has been assumed that imprinting effects in mammals and plants may have evolved independently from each other. In the animal kingdom, genomic imprinting might be a mode of gene regulation specific for mammalian species and has been suggested to be associated with a specific linkage/clustering of these genes. Hence, the mammalian genome should either show a special arrangement of imprinted genes or carry special DNA elements (such as imprinting control elements, ICs) that are responsible for the regulation of imprinting and are presumably absent in other nonimprinted species. Comparing mammalian imprinted genes to their homologs in nonmammalian species might be helpful for the identification of such elements.The Beckwith-Wiedemann syndrome (BWS) region currently represents the best investigated imprinting domain in the human and mouse genomes Ishihara et al. 2000;Onyango et al. 2000;Paulsen et al. 2000). In both species the region encompasses at least 10 imprinted genes. In human, the BWS region resides on chromosome 11p15.5 c...

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Insulator and silencer sequences in the imprinted region of human chromosome 11p15.5

Cited by 57 publications

References 62 publications

Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

Developmental Profile of H19 Differentially Methylated Domain (DMD) Deletion Alleles Reveals Multiple Roles of the DMD in Regulating Allelic Expression and DNA Methylation at the Imprinted H19/Igf2 Locus

Evolution of the Beckwith-Wiedemann syndrome region in vertebrates

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