PEG3 (paternally expressed 3)

2010-08-01   Yinhua 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

Identity

HGNC
LOCATION
19q13.43
LOCUSID
ALIAS
PW1,ZKSCAN22,ZNF904,ZSCAN24

DNA/RNA

Atlas Image
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).

Proteins

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

Entity name
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 name
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 name
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 name
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

Pubmed IDLast YearTitleAuthors
181662812008Imprinting of an evolutionarily conserved antisense transcript gene APeg3.Choo JH et al
160237062005Biallelic methylation and silencing of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines.Dowdy SC et al
182865292008Imprinted 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 et al
113316202001Paternal monoallelic expression of PEG3 in the human placenta.Hiby SE et al
200649272010The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth.Jiang X et al
119437802002Peg3/Pw1 is a mediator between p53 and Bax in DNA damage-induced neuronal death.Johnson MD et al
91499481997The human homolog of a mouse-imprinted gene, Peg3, maps to a zinc finger gene-rich region of human chromosome 19q13.4.Kim J et al
125546782003Methylation-sensitive binding of transcription factor YY1 to an insulator sequence within the paternally expressed imprinted gene, Peg3.Kim J et al
112602672001Tumour suppressor activity of human imprinted gene PEG3 in a glioma cell line.Kohda T et al
113981922001Epigenetic silencing of PEG3 gene expression in human glioma cell lines.Maegawa S et al
111618032001Imprinting of PEG3, the human homologue of a mouse gene involved in nurturing behavior.Murphy SK et al
193670872009Aberrant promoter methylation and expression of the imprinted PEG3 gene in glioma.Otsuka S et al
106814242000Pw1/Peg3 is a potential cell death mediator and cooperates with Siah1a in p53-mediated apoptosis.Relaix F et al
116771522001The 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 et al

Other Information

Locus ID:

NCBI: 5178
MIM: 601483
HGNC: 8826
Ensembl: ENSG00000198300

Variants:

dbSNP: 5178
ClinVar: 5178
TCGA: ENSG00000198300
COSMIC: PEG3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000198300ENST00000326441Q9GZU2
ENSG00000198300ENST00000593695Q9GZU2
ENSG00000198300ENST00000594389M0QXG1
ENSG00000198300ENST00000598410Q9GZU2
ENSG00000198300ENST00000599534Q9GZU2
ENSG00000198300ENST00000599577Q9GZU2
ENSG00000198300ENST00000600833M0QZD4
ENSG00000198300ENST00000647621A0A3B3IRU6
ENSG00000198300ENST00000647852A0A3B3ISL2
ENSG00000198300ENST00000648694Q9GZU2
ENSG00000198300ENST00000649233Q9GZU2
ENSG00000198300ENST00000649428Q9GZU2
ENSG00000198300ENST00000649680Q9GZU2
ENSG00000198300ENST00000649735A0A3B3ITJ6
ENSG00000198300ENST00000649876Q9GZU2
ENSG00000198300ENST00000650102Q9GZU2
ENSG00000198300ENST00000650632Q9GZU2

Expression (GTEx)

0
50
100
150
200
250
300
350

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
182865292008Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation.74
237983852013Decorin causes autophagy in endothelial cells via Peg3.70
200649272010The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth.53
234185532013Associations between methylation of paternally expressed gene 3 (PEG3), cervical intraepithelial neoplasia and invasive cervical cancer.44
231515312013Folate in pregnancy and imprinted gene and repeat element methylation in the offspring.43
160237062005Biallelic methylation and silencing of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines.35
193979552009DNA methylation analysis of the mammalian PEG3 imprinted domain.28
198345352009Sequential use of transcriptional profiling, expression quantitative trait mapping, and gene association implicates MMP20 in human kidney aging.27
119437802002Peg3/Pw1 is a mediator between p53 and Bax in DNA damage-induced neuronal death.22
257516512015PW1/Peg3 expression regulates key properties that determine mesoangioblast stem cell competence.21

Citation

Yinhua Yu ; Weiwei Feng ; Zhen Lu ; Robert C Bast Jr

PEG3 (paternally expressed 3)

Atlas Genet Cytogenet Oncol Haematol. 2010-08-01

Online version: http://atlasgeneticsoncology.org/gene/41690/peg3