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PEG3 (paternally expressed 3)

Written2010-08Yinhua Yu, Weiwei Feng, Zhen Lu, Robert C Bast Jr
The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 354, Houston, TX 77030, USA

(Note : for Links provided by Atlas : click)

Identity

Other aliasDKFZp781A095
KIAA0287
PW1
ZNF904
ZSCAN24
LocusID (NCBI) 5178
Atlas_Id 41690
Location 19q13.43  [Link to chromosome band 19q13]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

 
  Figure A. PEG3 DNA located on chromosome 19, starts at 62013257 and ends at 62043906 bp.
Figure B. The PEG3 gene contains 7-10 exons with 5 different transcripts.
Figure C. PEG3 promoter and first exon. The transcription start site and direction are indicated with an arrow. The horizontal bars are 32 CpG sites. The dark blue box is a CpG island surrounded the first exon (Figure modified from Feng et al., 2008).
Description Human PEG3 was originally identified as an ortholog of murine Peg3 that is the first imprinted gene detected in mouse chromosome 7. Human PEG3 is located ~2 Mb proximal of the 19q telomere, which is rich in Krüppel-type ZNF genes (Kim et al., 1997). Bisulfite sequencing across PEG3 revealed that all CpG dinucleotides examined were differentially methylated in human fetal brain, kidney, liver, and pancreas. PEG3 is monoallelically expressed during fetal development, it is a maternal-imprinted gene (Murphy et al., 2001).
Transcription The PEG3 gene contains 7-10 exons with 5 different transcripts.
Pseudogene There are no known pseudogenes, but an antisense transcript gene (APEG3), which is transcribed in the opposite direction of PEG3, has been identified from human. It is confirmed the presence of APEG3 in total RNAs from brain thalamus and testis. The functional significance of APEG3 is not known. The paternal allele-specific expression of anti-sense Peg3 (imprinting) was detected in mouse brain, but not in human yet (Choo et al., 2002).

Protein

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).

Mutations

Note Mutations have not been detected.

Implicated in

Note
  
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).
  
  
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).
  
  
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).
  
  
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).
  

Bibliography

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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 

Citation

This paper should be referenced as such :
Yu, Y ; Feng, W ; Lu, Z ; Bast, RC Jr
PEG3 (paternally expressed 3)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(5):422-424.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/PEG3ID41690ch19q13.html


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AtlasPEG3ID41690ch19q13.txt
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SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)5178
Protein : pattern, domain, 3D structure
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