Igf2 imprinting in development and disease

Reik, Wolf; Constância, Miguel; Dean, Wendy; Davies, Karen; Bowden, Lucy; Murrell, Adele; Feil, Robert; Walter, Joern; Kelsey, Gavin

doi:10.1007/978-3-0348-8484-6_8

Cited by 62 publications

(60 citation statements)

References 50 publications

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“…However, IGF2R does not transduce a signal; rather, it serves mainly to limit IGF2 bioavailability by targeting IGF2 for degradation (reviewed in [48]). Interestingly, the IGF2R gene is also imprinted-but it is maternally expressed (reviewed in [16]). …”

Section: The Igf2 Protein 31 Igf System Overviewmentioning

confidence: 99%

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IGF2: Epigenetic regulation and role in development and disease

Chao

D'Amore

2008

Cytokine & Growth Factor Reviews

281

221

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Insulin-like growth factor II (IGF2) is perhaps the most intricately regulated of all growth factors characterized to date. Its gene is imprinted-only one allele is active, depending on parental origin -and this pattern of expression is maintained epigenetically in almost all tissues. IGF2 activity is further controlled through differential expression of receptors and IGF-binding proteins (IGFBPs) that determine protein availability. This complex and multifaceted regulation emphasizes the importance of accurate IGF2 expression and activity. This review will examine the regulation of the IGF2 gene and what it has revealed about the phenomenon of imprinting, which is frequently disrupted in cancer. IGF2 protein function will be discussed, along with diseases that involve IGF2 overexpression. Roles for IGF2 in sonic hedgehog (Shh) signaling and angiogenesis will also be explored.

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Section: The Igf2 Protein 31 Igf System Overviewmentioning

confidence: 99%

“…However, IGF2 is the predominant IGF in adult humans (reviewed in [15]), and inappropriate IGF2 expression is implicated in a growing number of diseases (reviewed in [16]). The importance of IGF2 is highlighted by its complex and multifaceted regulation.…”

Section: Introductionmentioning

confidence: 99%

IGF2: Epigenetic regulation and role in development and disease

Chao

D'Amore

2008

Cytokine & Growth Factor Reviews

281

221

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“…H19DMR regulates the expression of two oppositely imprinted genes: 10 H19 encodes an untranslated RNA with tumour suppressor activity 11 and it is expressed from the maternal allele; insulin growth factor 2 (IGF2) encodes a growth factor essential for development 12 and it is expressed from the paternal allele. H19DMR harbours several CTCF-(CCCTC-binding factor) binding sites.…”

Section: Introductionmentioning

confidence: 99%

Analysis of H19 methylation in control and abnormal human embryos, sperm and oocytes

et al. 2011

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ART is suspected to generate increased imprinting errors in the lineage. Following an intra cytoplasmic sperm injection (ICSI) procedure, a certain number of embryos fail to develop normally and imprinting disorders may be associated to the developmental failure. To evaluate this hypothesis, we analysed the methylation profile of H19DMR, a paternally imprinting control region, in high-graded blastocysts, in embryos showing developmental anomalies, in the matching sperm and in oocytes of the concerned couples when they were available. Significant hypomethylation of the paternal allele was observed in half of the embryos, independently of the stage at which they were arrested (morula, compacted morula, pre blastocyst or BC-graded blastocysts). Conversely, some embryos showed significant methylation on the maternal allele, whereas few others showed both hypomethylation of the paternal allele and abnormal methylation of the maternal allele. The matching sperm at the origin of the embryos exhibited normal methylated H19 patterns. Thus, hypomethylation of the paternal allele in the embryos does not seem inherited from the sperm but likely reflects instability of the imprint during the demethylating process, which occurred in the early embryo. Analysis of a few oocytes suggests that the defect in erasure of the paternal imprint in the maternal germ line may be responsible for the residual methylation of the maternal allele in some embryos. None of these imprinting alterations could be related to a particular stage of developmental arrest; compared with high-grade blastocysts, embryos with developmental failure are more likely to have abnormal imprinting at H19 (Po0.05).

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“…IGF2 encodes a potent mitogenic growth factor that is active in early development and plays an important role in embryonic and fetal growth (4). IGF2 binds to the IGF-I receptor to initiate intracellular signaling cascades that lead to cell proliferation (5,6).…”

Section: Introductionmentioning

confidence: 99%

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

Murphy

Huang

Wen

et al. 2006

Molecular Cancer Research

127

103

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Overexpression of the imprinted insulin-like growth factor-II (IGF2) is a prominent characteristic of gynecologic malignancies. The purpose of this study was to determine whether IGF2 loss of imprinting (LOI), aberrant H19 expression, and/or epigenetic deregulation of the IGF2/H19 imprinted domain contributes to elevated IGF2 expression in serous epithelial ovarian tumors. IGF2 LOI was observed in 5 of 23 informative serous epithelial ovarian cancers, but this did not correlate with elevated expression of IGF2 H19 RNA expression levels were also found not to correlate with IGF2 transcript levels. However, we identified positive correlations between elevated IGF2 expression and hypermethylation of CCCTC transcription factor binding sites 1 and 6 at the H19 proximal imprint center (P = 0.05 and 0.02, respectively). Hypermethylation of CCCTC transcription factor sites 1 and 6 was observed more frequently in cancer DNA compared with lymphocyte DNA obtained from women without malignancy (P < 0.0001 for both sites 1 and 6). Ovarian cancers were also more likely to exhibit maternal allele-specific hypomethylation upstream of the imprinted IGF2 promoters when compared with normal lymphocyte DNA (P = 0.004). This is the same region shown previously to be hypomethylated in colon cancers with IGF2 LOI, but this was not associated with LOI in ovarian cancers. Elevated IGF2 expression is a frequent event in serous ovarian cancer and this occurs in the absence of IGF2 LOI. These data indicate that the epigenetic changes observed in these cancers at the imprint center may contribute to IGF2 overexpression in a novel mechanistic manner. (Mol Cancer Res 2006;4(4):283 -92)

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Igf2 imprinting in development and disease

Cited by 62 publications

References 50 publications

IGF2: Epigenetic regulation and role in development and disease

IGF2: Epigenetic regulation and role in development and disease

Analysis of H19 methylation in control and abnormal human embryos, sperm and oocytes

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

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