| Description | PEG3 is maternal-imprinted and paternally expressed. The imprinted status of PEG3 throughout development and adult life. PEG3 may be a susceptibility locus for cancer and for neurobehavioral deficits (Murphy et al., 2001). |
| Expression | PEG3 is expressed at higher levels in ovary and placenta (Kim et al., 1997; Hiby et al., 2001). It was also strongly expressed in the adult brain (Kohda et al., 2001). |
| Localisation | High levels of PEG3 have localized to the layer of villous cytotrophoblast cells in the human placenta, PEG3 expression is also detected in the ovary stroma (Hiby et al., 2001). |
| Function | PEG3 is an imprinted gene expressed exclusively from the paternal allele. The precise function of PEG3 is not clear, but recent evidence suggests that it plays an important role in the p53/c-myc-mediated apoptosis pathway.
PEG3 is a maternally imprinted tumor suppressor gene that is downregulated in gliomas, ovarian cancers, breast cancers and other gynecologic cancers (Kohda et al., 2001; Dowdy et al., 2005; Feng et al., 2008).
There are several studies revealed murine Peg3 acts as an intermediary between p53 and Bax in a cell death pathway activated by DNA damage in primary mouse cortical neurons, inhibiting Peg3 activity blocks p53-induced apoptosis (Johnson et al., 2002). Pw1/Peg3 interacts with a p53-inducible gene product Siah1a. Coexpression of Pw1/Peg3 with Siah1a induces apoptosis independently of p53. Inhibiting Pw1/Peg3 activity blocks p53-induced apoptosis (Relaix et al., 2000). Since human PEG3 is highly conserved with murine Peg3, PEG3 may have same function, Jiang et al. (2010) demonstrated that enforced overexpression of PEG3 mRNA during zebrafish embryogenesis decreased beta-catenin protein expression and inhibited Wnt-dependent tail development. Peg3/Pw1 also inhibited Wnt signaling in human cells by binding to beta-catenin and promoting its degradation via a p53/Siah1-dependent, GSK3beta-independent proteasomal pathway. Hypermethylation of the PEG3 promoter in primary human gliomas led to a loss of imprinting and decreased PEG3 mRNA expression that correlated with increasing tumor grade (Jiang et al., 2010).
The transcription factor YY1 can bind to the first intron of human PEG3, and specifically to the paternal allele of the gene. YY1-binding sites are methylated only on the maternal chromosome. YY1-binding region may function as a methylation-sensitive insulator that could influence the imprinted expression of PEG3 (Kim et al., 2003). |
| Homology | Human PEG3 is known to have orthologs in mice and cow. Human PEG3 gene sequences revealed a high level of conservation with Murine Peg3 (83% similarity), but one of the two proline-rich repeats is absent from the human PEG3 (Kim et al., 1997). |
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| Entity | Glioma, glioblastoma |
| Note | A significant decrease in PEG3 expression was more commonly observed in glioma cell lines as compared with that in primary cultures of astrocytes. Transfection of PEG3 cDNA in a glioma cell line resulted in a loss of tumorigenicity in nude mice (Kohda et al., 2001). The epigenetic silencing of PEG3 expression in glioma cell lines depends on aberrant DNA methylation of an exonic CpG island. Treatment of glioma cell lines with the DNA demethylating agent 5-aza-2'-deoxycytidine reversed the silencing of PEG3 biallelically (Maegawa et al., 2001). Re-expression of PEG3 in glioma cells suppresses their proliferation. Hypermethylation of the PEG3 promoter in primary human gliomas led to a loss of imprinting and decreased PEG3 mRNA expression that correlated with tumor grade (Jiang et al., 2010). The lower gene expression was confirmed statistically in glioblastoma (Otsuka et al., 2009). |
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| Entity | Endometrial cancer, cervical cancer, choriocarcinomas |
| Note | PEG3 is silenced in all endometrial and cervical cancer cell lines studied. In contrast, loss of maternal imprinting and relatively high PEG3 expression levels were detected in all four choriocarcinomas cell lines studied (Dowdy et al., 2005). |
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| Entity | Breast cancer, ovarian cancer |
| Note | Five of the eight ovarian cancer cell lines were found to be PEG3 negative, the remaining three express low levels of PEG3 mRNA (Dowdy et al., 2005). PEG3 was down-regulated in 75% of ovarian cancers. PEG3 was hypermethylated in 11 of 42 ovarian cancers (26%), and PEG3 expression was down-regulated in 10 of those 11 cancers. LOH was detected in 5 of 25 informative cases for PEG3 (20%). Re-expression of PEG3 markedly inhibited ovarian cancer growth. PEG3 expression could be restored by treatment with 5-aza-2'-deoxycytidine and trichostatin A (Feng et al., 2008). |
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| Entity | Hydatidiform moles |
| Note | PEG3 is not mutated in women with familial recurrent hydatidiform moles, there is allele-specific methylation of the CpG island and expression from the paternal allele in two independent informative pedigrees (Van den Veyver et al., 2001). |
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| Imprinting of an evolutionarily conserved antisense transcript gene APeg3. |
| Choo JH, Kim JD, Kim J. |
| Gene. 2008 Feb 15;409(1-2):28-33. Epub 2007 Nov 21. |
| PMID 18166281 |
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| Biallelic methylation and silencing of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines. |
| Dowdy SC, Gostout BS, Shridhar V, Wu X, Smith DI, Podratz KC, Jiang SW. |
| Gynecol Oncol. 2005 Oct;99(1):126-34. |
| PMID 16023706 |
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| Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation. |
| Feng W, Marquez RT, Lu Z, Liu J, Lu KH, Issa JP, Fishman DM, Yu Y, Bast RC Jr. |
| Cancer. 2008 Apr 1;112(7):1489-502. |
| PMID 18286529 |
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| Paternal monoallelic expression of PEG3 in the human placenta. |
| Hiby SE, Lough M, Keverne EB, Surani MA, Loke YW, King A. |
| Hum Mol Genet. 2001 May 1;10(10):1093-100. |
| PMID 11331620 |
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| The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth. |
| Jiang X, Yu Y, Yang HW, Agar NY, Frado L, Johnson MD. |
| J Biol Chem. 2010 Mar 12;285(11):8472-80. Epub 2010 Jan 11. |
| PMID 20064927 |
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| Peg3/Pw1 is a mediator between p53 and Bax in DNA damage-induced neuronal death. |
| Johnson MD, Wu X, Aithmitti N, Morrison RS. |
| J Biol Chem. 2002 Jun 21;277(25):23000-7. Epub 2002 Apr 9. |
| PMID 11943780 |
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| The human homolog of a mouse-imprinted gene, Peg3, maps to a zinc finger gene-rich region of human chromosome 19q13.4. |
| Kim J, Ashworth L, Branscomb E, Stubbs L. |
| Genome Res. 1997 May;7(5):532-40. |
| PMID 9149948 |
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| Methylation-sensitive binding of transcription factor YY1 to an insulator sequence within the paternally expressed imprinted gene, Peg3. |
| Kim J, Kollhoff A, Bergmann A, Stubbs L. |
| Hum Mol Genet. 2003 Feb 1;12(3):233-45. |
| PMID 12554678 |
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| Tumour suppressor activity of human imprinted gene PEG3 in a glioma cell line. |
| Kohda T, Asai A, Kuroiwa Y, Kobayashi S, Aisaka K, Nagashima G, Yoshida MC, Kondo Y, Kagiyama N, Kirino T, Kaneko-Ishino T, Ishino F. |
| Genes Cells. 2001 Mar;6(3):237-47. |
| PMID 11260267 |
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| Epigenetic silencing of PEG3 gene expression in human glioma cell lines. |
| Maegawa S, Yoshioka H, Itaba N, Kubota N, Nishihara S, Shirayoshi Y, Nanba E, Oshimura M. |
| Mol Carcinog. 2001 May;31(1):1-9. |
| PMID 11398192 |
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| Imprinting of PEG3, the human homologue of a mouse gene involved in nurturing behavior. |
| Murphy SK, Wylie AA, Jirtle RL. |
| Genomics. 2001 Jan 1;71(1):110-7. |
| PMID 11161803 |
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| Aberrant promoter methylation and expression of the imprinted PEG3 gene in glioma. |
| Otsuka S, Maegawa S, Takamura A, Kamitani H, Watanabe T, Oshimura M, Nanba E. |
| Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(4):157-65. |
| PMID 19367087 |
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| Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis. |
| Relaix F, Wei X, Li W, Pan J, Lin Y, Bowtell DD, Sassoon DA, Wu X. |
| Proc Natl Acad Sci U S A. 2000 Feb 29;97(5):2105-10. |
| PMID 10681424 |
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| The human homologue (PEG3) of the mouse paternally expressed gene 3 (Peg3) is maternally imprinted but not mutated in women with familial recurrent hydatidiform molar pregnancies. |
| Van den Veyver IB, Norman B, Tran CQ, Bourjac J, Slim R. |
| J Soc Gynecol Investig. 2001 Sep-Oct;8(5):305-13. |
| PMID 11677152 |
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