Other entities represented in this entry:
HGNC Approved Gene Symbol: PEG3
Cytogenetic location: 19q13.43 Genomic coordinates (GRCh38): 19:56,810,082-56,840,726 (from NCBI)
The human PEG3 and ZIM2 transcripts share 5-prime exons and a common promoter, and both are paternally expressed. In contrast, Peg3 and Zim2 are individual genes that do not share promoters or exons in mouse and cow, and Zim2 is expressed biallelically in mouse and cow testis. The human PEG3 and ZIM2 transcripts both encode zinc finger proteins (Kim et al., 2004).
In a systematic screen for imprinted genes in the mouse, Kaneko-Ishino et al. (1995) identified a gene they called Peg1 (paternally expressed gene 1; 601029) on chromosome 6 and reported another apparently imprinted gene which they designated Peg3. Kuroiwa et al. (1996) further described the 9-kb Peg3 gene transcript, which encodes an unusual zinc finger protein of 1,572 amino acids. The protein has 11 widely spaced C2H2-like zinc finger motifs and 2 groups of amino acid repeats of approximately 7 to 10 residues with no known function. Peg3 is expressed in early somites, branchial arches, and other mesodermal tissues, as well as in the hypothalamus.
By BAC analysis and RT-PCR and RACE of a testis cDNA library, Kim et al. (2000) cloned a PEG3 splice variant that they called ZIM2. The ZIM2 transcript is formed when the first 7 exons of PEG3 are spliced to 4 downstream exons derived from an ancestral ZIM2 gene (see EVOLUTION). The deduced 527-amino acid ZIM2 protein contains a central KRAB A domain and a C-terminal Kruppel-type (C2H2) zinc finger domain consisting of 5 complete and 2 degenerate finger units. Northern blot analysis detected a 2.5-kb ZIM2 transcript in testis only and a 9-kb ZIM2 transcript in adult testis and in fetal kidney and brain. Competitive RT-PCR of adult tissues detected the PEG3 transcript in placenta, testis, and brain and the ZIM2 transcript in testis only.
Kim et al. (1997) reported that the PEG3 gene, like other genes within the region on 19q to which it maps, also encodes a Kruppel-type ZNF protein, but one that is distinguished from other ZNF gene products by the fact that it carries 2 novel proline-rich motifs. The mouse and partial human PEG3 gene sequences showed a high level of conservation, despite that fact that 1 of the 2 proline-rich repeats is absent from the human gene. Kim et al. (1997) found that the human gene is expressed at highest levels in ovary and placenta; mouse Peg3, by contrast, is transcribed at highest levels in the adult brain.
Tumor necrosis factor (TNF; 191160) mediates a variety of biologic activities, including cell proliferation, differentiation, and programmed cell death. The specific response to TNF depends upon cell type and reflects the presence of specific regulatory proteins that participate in the TNF response pathway. TNF signal transduction is mediated by TRAF2 (601895), which binds the TNF receptor-2 (TNFR2; 191191) and activates NF-kappa-B (NFKB1; 164011). Relaix et al. (1998) found that the gene they had previously identified and called Pw1 is identical to Peg3. They reported that Peg3 associates specifically with TRAF2 but not with other TRAF family members. Peg3 expression activates NF-kappa-B via dissociation and acts synergistically with TRAF2. Transfection of a truncated Peg3 containing the TRAF2 interaction site abolished NF-kappa-B activation by TRAF2 and/or TNF. Relaix et al. (1998) concluded that Peg3 is a regulator of the TNF response.
Kohda et al. (2001) found that a significant decrease in PEG3 expression was more commonly observed in glioma cell lines than in primary cultures of astrocytes. Transfection of PEG3 cDNA in a glioma cell line resulted in a loss of tumorigenicity in nude mice.
Using RT-PCR, Northern blot, and in situ hybridization, Hiby et al. (2001) demonstrated high levels of PEG3 in the human placenta and localized the signal to the layer of villous cytotrophoblast cells. In contrast, the pattern of expression of Peg3 in the mouse placenta was less restricted, the message being present in all trophoblast populations. By utilizing a polymorphism detected in exon 9, the authors established that only the paternal allele is expressed in human placenta; thus human PEG3 is maternally imprinted as in mouse.
The 5-prime end of murine Peg3 is associated with a CpG island that exhibits allele-specific methylation (Lucifero et al., 2002). By DNA mobility shift and chromatin immunoprecipitation (ChIP) assays, Kim et al. (2003) demonstrated that YY1 (600013), a Gli-type transcription factor, binds to an evolutionarily conserved motif in intron 1 of Peg3. The YY1 binding site contains 1 CpG dinucleotide, and methylation of this CpG site abolished the binding activity of YY1 in vitro. The Peg3 YY1 binding sites are methylated only on the maternal chromosome in vivo, and ChIP assays confirmed that YY1 binds specifically to the paternal allele of the gene. Promoter, enhancer, and insulator assays with deletion constructs of sequence surrounding the YY1 binding sites indicated that the region functions as a methylation-sensitive insulator that may influence the imprinted expression of Peg3 and neighboring genes. The authors suggested a potential role of YY1 in mammalian genomic imprinting.
Kim et al. (2000) determined that the PEG3 gene contains 13 exons, the last 4 of which originated from the ancestral ZIM2 gene. The initiation codon is located in exon 3.
Kuroiwa et al. (1996) mapped Peg3 to the proximal region of mouse chromosome 7, a region that shows homology of synteny with human 19q13.1-q13.3. Kuroiwa et al. (1996) also noted that in the mouse, maternal duplication of proximal chromosome 7 causes neonatal lethality.
Because imprinting is generally conserved among mammals, and imprinted domains generally encompass several adjacent genes, expression patterns and chromosomal environment of the human counterpart of Peg3 was of interest. Kim et al. (1997) localized the human PEG3 gene approximately 2 Mb proximal to the telomere of 19q, within a region known to carry large numbers of tandemly clustered Kruppel-type zinc finger-containing (ZNF) genes.
Kim et al. (2000) mapped the mouse PEG3 gene to proximal chromosome 7.
Human evolution is characterized by a dramatic increase in brain size and complexity. To probe its genetic basis, Dorus et al. (2004) examined the evolution of genes involved in diverse aspects of nervous system biology. These genes, including PEG3, displayed significantly higher rates of protein evolution in primates than in rodents. This trend was most pronounced for the subset of genes implicated in nervous system development. Moreover, within primates, the acceleration of protein evolution was most prominent in the lineage leading from ancestral primates to humans. Dorus et al. (2004) concluded that the phenotypic evolution of the human nervous system has a salient molecular correlate, i.e., accelerated evolution of the underlying genes, particularly those linked to nervous system development.
In humans, the PEG3 and ZIM2 transcripts share 5-prime exons and a common promoter, and both are paternally expressed. However, Kim et al. (2004) demonstrated that Peg3 and Zim2 are individual genes in mouse and cow. They found that a recent insertional event placed unrelated genes, Zim1 and Ast1, between the Peg3 and Zim2 genes of mouse and cow, respectively. In both species, the 3 genes have individual promoters, and only Peg3 is expressed exclusively from the paternal allele. Kim et al. (2004) concluded that exon sharing of human PEG3 and ZIM2 likely represents a fusion event that joined the genes and brought ZIM2 under paternal expression control.
Somatic Mutation of ZIM2 in Pancreatic Cancer
Biankin et al. (2012) performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort of 142 patients with early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumors identified substantial heterogeneity with 2,016 nonsilent mutations and 1,628 copy number variations. Biankin et al. (2012) defined 16 significantly mutated genes, reaffirming known mutations and uncovering novel mutated genes including additional genes involved in chromatin modification (EPC1, 610999 and ARID2, 609539), DNA damage repair (ATM; 607585), and other mechanisms (ZIM2; MAP2K4, 601335; NALCN, 611549; SLC16A4, 603878; and MAGEA6, 300176). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signaling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. Biankin et al. (2012) also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO (see 603742) signaling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
Li et al. (1999) disrupted the Peg3 gene in mice. The heterozygous mice that inherited the mutant allele from the paternal germline were smaller, but otherwise fertile, healthy, and normal in their general behavior. Only 8% of first litters of mutant mothers grew to weaning age. Mutant mothers exhibited very abnormal maternal behavior and also had deficient milk ejection due to reduced numbers of oxytocin neurons in the hypothalamus.
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Hiby, S. E., Lough, M., Keverne, E. B., Surani, M. A., Loke, Y. W., King, A. Paternal monoallelic expression of PEG3 in the human placenta. Hum. Molec. Genet. 10: 1093-1100, 2001. [PubMed: 11331620] [Full Text: https://doi.org/10.1093/hmg/10.10.1093]
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Kim, J., Ashworth, L., Branscomb, E., Stubbs, L. The human homolog of a mouse-imprinted gene, Peg3, maps to a zinc finger gene-rich region of human chromosome 19q13.4. Genome Res. 7: 532-540, 1997. [PubMed: 9149948] [Full Text: https://doi.org/10.1101/gr.7.5.532]
Kim, J., Bergmann, A., Lucas, S., Stone, R., Stubbs, L. Lineage-specific imprinting and evolution of the zinc-finger gene ZIM2. Genomics 84: 47-58, 2004. [PubMed: 15203203] [Full Text: https://doi.org/10.1016/j.ygeno.2004.02.007]
Kim, J., Bergmann, A., Stubbs, L. Exon sharing of a novel human zinc-finger gene, ZIM2, and paternally expressed gene 3 (PEG3). Genomics 64: 114-118, 2000. [PubMed: 10708526] [Full Text: https://doi.org/10.1006/geno.1999.6112]
Kim, J., Kollhoff, A., Bergmann, A., Stubbs, L. Methylation-sensitive binding of transcription factor YY1 to an insulator sequence within the paternally expressed imprinted gene, Peg3. Hum. Molec. Genet. 12: 233-245, 2003. [PubMed: 12554678] [Full Text: https://doi.org/10.1093/hmg/ddg028]
Kohda, T., Asai, A., Kuroiwa, Y., Kobayashi, S., Aisaka, K., Nagashima, G., Yoshida, M. C., Kondo, Y., Kagiyama, N., Kirino, T., Kaneko-Ishino, T., Ishino, F. Tumour suppressor activity of human imprinted gene PEG3 in a glioma cell line. Genes Cells 6: 237-247, 2001. [PubMed: 11260267] [Full Text: https://doi.org/10.1046/j.1365-2443.2001.00412.x]
Kuroiwa, Y., Kaneko-Ishino, T., Kagitani, F., Kohda, T., Li, L.-L., Tada, M., Suzuki, R., Yokoyama, M., Shiroishi, T., Wakana, S., Barton, S. C., Ishino, F., Surani, M. A. Peg3 imprinted gene on proximal chromosome 7 encodes for a zinc finger protein. Nature Genet. 12: 186-190, 1996. [PubMed: 8563758] [Full Text: https://doi.org/10.1038/ng0296-186]
Li, L.-L., Keverne, E. B., Aparicio, S. A., Ishino, F., Barton, S. C., Surani, M. A. Regulation of maternal behavior and offspring growth by paternally expressed Peg3. Science 284: 330-333, 1999. [PubMed: 10195900] [Full Text: https://doi.org/10.1126/science.284.5412.330]
Lucifero, D., Mertineit, C., Clarke, H. J., Bestor, T. H., Trasler, J. M. Methylation dynamics of imprinted genes in mouse germ cells. Genomics 79: 530-538, 2002. [PubMed: 11944985] [Full Text: https://doi.org/10.1006/geno.2002.6732]
Relaix, F., Wei, X., Wu, X., Sassoon, D. A. Peg3/Pw1 is an imprinted gene involved in the TNF-NF-kappa-B signal transduction pathway. Nature Genet. 18: 287-291, 1998. [PubMed: 9500555] [Full Text: https://doi.org/10.1038/ng0398-287]