A maternally methylated CpG island in
            <i>KvLQT1</i>
            is associated with an antisense paternal transcript and loss of imprinting in Beckwith–Wiedemann syndrome

Smilinich, Nancy J.; Day, Colleen D.; Fitzpatrick, Galina V.; Caldwell, Germaine; Lossie, Amy C.; Cooper, Paul R.; Smallwood, Allan C.; Joyce, Johanna A.; Schofield, Paul N.; Reik, Wolf; Nicholls, Robert D.; Weksberg, Rosanna; Driscoll, Daniel J.; Maher, Eamonn R.; Shows, Thomas B.; Higgins, Michael J.

doi:10.1073/pnas.96.14.8064

Cited by 397 publications

(352 citation statements)

References 56 publications

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“…One putative CTCF binding site was identified containing 11 of 16 bases identical to conserved CTCF binding sites 29 . Two EagI sites previously examined for parent-of-origin methylation are shown 30 The conditions for second-round PCR were 3 min at 95 °C and then 36 cycles of 45 s at 95°C, 60°C and 72°C. All reactions included 10% dimethylsulfoxide and 1.5 mM MgCl 2 .…”

Section: Methodsmentioning

confidence: 99%

Genome imprinting regulated by the mouse Polycomb group protein Eed

et al. 2003

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Epigenetic regulation is essential for temporal, tissue-specific and parent-of-origin-dependent gene expression. It has recently been found that the mouse Polycomb group (PcG) gene Eed (embryonic ectoderm development) acts to maintain repression of the imprinted X chromosome. Here, we investigated whether Eed is also required for regulation of autosomal imprinted loci. Expression analyses showed that transcripts from the silent alleles of a subset of paternally repressed genes were present in Eed -/-embryos. Parent-of-origin methylation was preserved in these embryos, but we observed changes in the methylation status of specific CpGs in differentially methylated regions (DMRs) at affected but not at unaffected loci. These data identify Eed as a member of a new class of trans-acting factors that regulate parent-of-origin expression at imprinted loci.A subset of the mouse and human genomes is expressed from only one allele in a parent-oforigin-specific manner. This subset includes imprinted X-chromosome inactivation and autosomal imprinted loci. It has been proposed that this epigenetic regulation is accomplished through covalent modifications of both the DNA and the N-terminal tails of core histones in nucleosomes 1,2 . There are more than 60 identified autosomal imprinted genes, about half of which are paternally repressed and half maternally repressed. Most imprinted genes that have been examined contain at least one DMR located in the 5′ promoter region or in the body of the gene itself 3 . Recently, several proteins (DNA methyltransferases, CpG methyl binding proteins, chromatin insulators) have been identified as trans-acting factors involved in the epigenetic regulation of these loci 4 . Many of these factors either possess or associate with proteins that possess DNA methyltransferase activity. Additionally, recent studies have shown correlations between covalent histone modifications and the transcriptional status of imprinted alleles 5 . In particular, methylation of histone H3 has been associated with the inactive X chromosome 6 .PcG protein complexes are thought to maintain long-term gene silencing during development through alterations of local chromatin structure 7 . In both Drosophila and mammals, recent reports have shown that the Eed/Ezh2 PcG complex contains histone methyltransferase (HMT) activity, methylating histone H3, and that mutations in the SET domain of the Ezh2 fly homolog, E(Z), abolish the enzymatic activity of the complex in vitro [8][9][10] . The Eed/Ezh2 complex has also been shown to interact with histone deacetylases (HDACs; ref. 11). These

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Section: Methodsmentioning

confidence: 99%

Genome imprinting regulated by the mouse Polycomb group protein Eed

et al. 2003

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“…In about half of the patients, there is loss of DNA methylation at the ICR controlling the KCNQ1 domain. This loss of methylation correlates with biallelic expression of the KCNQ1OT1 non-coding transcript, (25,26) and strongly reduced CDKN1C expression. (27,28) The reduced expression of CDKN1C, a growth-reducing factor, is thought to be causally involved in the syndrome.…”

Section: Introductionmentioning

confidence: 92%

Epigenetic deregulation of imprinting in congenital diseases of aberrant growth

2006

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“…In contrast, it is downregulated or virtually absent in the corresponding adult organs. Elevated levels of IGF-2 are characteristic for tumours originating from tissues expressing high levels of IGF-2-RNA during foetal life such as nephroblastoma (Wilm's tumour) (Reik and Maher, 1997), rhabdomyosarcoma (Ross et al, 2000), and HCC (Fiorentino et al, 1994) as well as in overgrowth disorders such as Beckwith -Wiedemann syndrome (Smilinich et al, 1999). High levels of IGF-2 peptide were detected in primary HCC and dysplastic foci of HCC-bearing livers compared to uninvolved liver tissue.…”

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confidence: 99%

Focal overexpression of insulin-like growth factor 2 by hepatocytes and cholangiocytes in viral liver cirrhosis

et al. 2003

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Insulin-like growth factor (IGF)-2 is overexpressed in hepatocellular carcinoma and accompanying dysplastic lesions. IGF-2 signalling is mediated through IGF-1 receptor (IGF-1R), while mannose 6-phosphate/insulin-like growth factor-2 receptor (M6P/IGF-2R) controls pericellular levels of free IGF-2. We studied, by in situ hybridisation and immunohistology, 18 liver specimens with cirrhosis of different aetiology without neoplastic or dysplastic lesions. Immunohistology was also performed for insulin receptor IGF-1R and IGF-binding proteins 3 and 4. High focal levels of IGF-2 RNA were found in some hepatocytes of all livers with HBV-or HCV-induced cirrhosis (n ¼ 10), but in only one of the cirrhoses with nonviral aetiology (n ¼ 8). IGF-2 was overexpressed in biliary duct epithelial cells in one case. Compared with noncirrhotic liver, all cirrhotic specimens showed reduced hepatocellular expression of M6P/IGF-2R protein, which contrasted with enhanced expression in perisinusoidal cells. Immunostaining for the other antigens did not reveal significant differences. Upregulation of IGF-2 in some hepatocytes may lead to high focal IGF-2 levels sufficient to saturate local IGF-2 binding capacities, and may result in an increased susceptibility to cellular dedifferentiation and, ultimately, liver cancer. Downregulation of hepatocellular M6P/IGF-2R and upregulation of IGF-2 seem to be early events in hepatocarcinogenesis prior to the appearance of morphologically distinct dysplastic lesions. Elevated focal IGF-2 transcript levels may therefore indicate an increased risk for hepatocellular and cholangiocellular carcinomas.

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A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith–Wiedemann syndrome

Cited by 397 publications

References 56 publications

Genome imprinting regulated by the mouse Polycomb group protein Eed

Genome imprinting regulated by the mouse Polycomb group protein Eed

Epigenetic deregulation of imprinting in congenital diseases of aberrant growth

Focal overexpression of insulin-like growth factor 2 by hepatocytes and cholangiocytes in viral liver cirrhosis

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