Alternative titles; symbols
HGNC Approved Gene Symbol: PLAGL1
Cytogenetic location: 6q24.2 Genomic coordinates (GRCh38) : 6:143,940,300-144,064,599 (from NCBI)
PLAGL1 encodes a zinc finger DNA-binding transcription factor that can regulate apoptosis and cell cycle arrest concurrently (summary by Valleley et al., 2007).
Spengler et al. (1997) isolated mouse Plagl1, which they designated Zac. The deduced 667-amino acid protein contains 7 C2H2 zinc fingers in its N-terminal half. Northern blot analysis of several mouse tissues detected highest Zac1 expression in pituitary.
Abdollahi et al. (1997) cloned Plagl1 through its loss of expression in a rat model of epithelial ovarian cancer and named it Lot1 for 'lost on transformation.' By searching databases for sequences similar to rat Lot1, followed by clone walking within a human fetal brain cDNA library, Abdollahi et al. (1997) obtained full-length human LOT1. The deduced 464-amino acid protein has a calculate molecular mass of 51 kD. In addition to 7 N-terminal zinc fingers, LOT1 contains proline- and glutamine-rich regions in its C-terminal half. Rat and human LOT1 share 67.7% amino acid identity overall, with 85.5% identity in the N-terminal zinc finger region. Northern blot analysis detected multiple LOT1 transcripts in all human tissues examined, including spleen, thymus, prostate, testis, ovary, intestine, colon, and leukocytes. Highest expression was detected in ovary.
By RT-PCR of normal human leukocytes, Valleley et al. (2007) detected 15 alternatively spliced ZAC transcripts that differed in the promoter used, the 5-prime noncoding exons included, and the presence or absence of protein-coding exon 7. The last protein-coding exon, exon 8, was detected in all transcripts. Transcripts lacking exon 7 encode a short ZAC isoform with only 5 zinc fingers. The short isoform was more frequently encoded by transcripts initiated at the upstream promoter region, P2, and the longer isoform was more frequently encoded by transcripts initiated at the downstream promoter, P1.
Spengler et al. (1997) found that mouse Zac inhibited tumor cell proliferation in vitro and in vivo in nude mice. They showed that these antiproliferative properties ensued from the regulation of 2 pathways critical to the activity of p53 (191170), i.e., cell cycle progression and apoptosis. Thus, mouse Zac was the first gene unrelated to p53 that was found to regulate these 2 fundamental genetic programs. The authors hypothesized that Zac also could share with p53 its tumor suppressor activity.
Varrault et al. (1998) showed that human ZAC had transactivation and DNA-binding activities. Furthermore, like its mouse counterpart and p53, ZAC inhibited tumor cell proliferation through induction of both apoptosis and cell cycle arrest.
Bilanges et al. (2001) found that the long and short ZAC isoforms showed the same antiproliferative activity. However, the long isoform was more efficient at inducing apoptosis, whereas the short isoform had a greater ability to induce cell cycle arrest.
Abdollahi et al. (1997) showed that LOT1 expression was lost in some human ovarian cancer cell lines.
Transient Neonatal Diabetes Mellitus 1
Kamiya et al. (2000) described a screen for novel imprinted human genes, and in this way identified the ZAC/PLAGL1 gene as a strong candidate for transient neonatal diabetes mellitus (TNDM1; 601410). To screen for imprinted genes, they compared parthenogenetic DNA from a chimeric patient FD and androgenetic DNA from hydatidiform mole, using restriction landmark genome scanning for methylation. This resulted in identification of 2 novel imprinted loci, one of which (NV149) mapped to the TNDM region of 6q24. From analysis of the corresponding genomic region, it was determined that NV149 lies approximately 60 kb upstream of the ZAC/PLAGL1 gene. RT-PCR analysis was used to confirm that the ZAC/PLAGL1 gene is expressed only from the paternal allele in a variety of tissues. TNDM is known to result from upregulation of a paternally expressed gene on 6q24. Kamiya et al. (2000) pointed to the paternal expression, map position, and known biologic properties of ZAC/PLAGL1 as making it highly likely that it is the TNDM gene. In particular, ZAC/PLAGL1 is a transcriptional regulator of the type-1 receptor for pituitary adenylate cyclase-activating polypeptide (102981), which is the most potent known insulin secretagogue and an important mediator of autocrine control of insulin secretion in the pancreatic islet.
Arima et al. (2001) showed that the differentially methylated CpG island that partially overlaps Zac1 and Hymai (606546) at the syntenic mouse locus is a likely imprinting control region (ICR) for the 120- to 200-kb domain. The region is unmethylated in sperm but probably methylated in oocytes, a difference that persists between parental alleles throughout pre- and postimplantation development. Within this ICR, there is a region that exhibits a high degree of homology between mouse and human and acts as a strong transcriptional repressor when methylated. In 5 of 6 TNDM patients studied with a normal karyotype, loss of methylation at 8 CpG sites within the region was demonstrated. The authors proposed that this ICR may regulate expression of imprinted genes within the domain, and that epigenetic or genetic mutations of this region probably result in TNDM by affecting expression of ZAC in the pancreas and/or the pituitary.
Arima et al. (2006) found that a transgene carrying the human HYMAI/PLAGL1 differentially methylated CpG island was methylated in the correct parent origin-specific manner in mice, and that this methylation was sufficient to confer imprinted expression from the transgene. They concluded that the differentially methylated CpG island functions as the imprinting center for the HYMAI/PLAGL1 imprinted domain.
Temple et al. (1995, 1996) showed that 2 genetic abnormalities of chromosome 6, paternal uniparental isodisomy of chromosome 6 and paternally inherited duplications of chromosome 6q, are associated with TNDM. They hypothesized that TNDM could result from inappropriate overexpression of a paternally expressed imprinted gene on 6q24. Mackay et al. (2002) demonstrated imprinted expression of the ZAC and HYMAI genes in cases of TNDM.
By meta-analysis of microarray data, Varrault et al. (2006) identified Zac1 as a member of a network of coregulated imprinted genes that control mouse embryonic growth. Zac1 reexpression in a mouse neuroblastoma cell line lacking Zac1 led to expression of several of these imprinted genes, including Igf2 (147470), H19 (103280), Cdkn1c (600856), and Dlk1 (176290), and Zac1 directly regulated the Igf2/H19 locus through binding to a shared enhancer.
Valleley et al. (2007) identified an alternative promoter region, P2, in the ZAC gene upstream of the differentially methylated promoter, P1. They showed that the CpG island of P2 was unmethylated and biallelically expressed. Quantitative real-time PCR detected variable expression of transcripts derived from both promoters in all human tissues examined. Transcripts containing imprinted P1 predominated in most tissues, while transcripts containing the biallelically expressed P2 predominated in leukocytes. Liver and spleen expressed transcripts from both promoters relatively equally. In all tissues examined, expression from P1 was monoallelic and expression from P2 was biallelic.
Valleley et al. (2007) determined that the PLAGL1 gene contains at least 8 exons and spans 125 kb. There are 2 alternative promoter regions separated by about 55 kb, and both lie within CpG islands. Exons 1 through 6 are untranslated and are subject to a complex pattern of alternative splicing. Coding exon 7 is also alternatively spliced.
By fluorescence in situ hybridization, Varrault et al. (1998) mapped the human ZAC gene to chromosome 6q24-q25, a region that shows allelic loss in breast and ovary cancers, melanomas, astrocytomas, and renal cell carcinomas, and is thus thought to harbor at least 1 tumor suppressor gene. The mouse gene maps to chromosome 10A2, a region syntenic to human 6q25.
Varrault et al. (2006) found that Zac1 knockdown in mice resulted in intrauterine growth restriction, altered bone formation, and neonatal lethality. As expected for a maternally repressed gene, Zac1 +/-(maternal) pups were indistinguishable from wildtype mice, whereas Zac +/-(paternal) pups displayed the weight reduction observed in Zac1 -/- pups.
Abdollahi, A., Godwin, A. K., Miller, P. D., Getts, L. A., Schultz, D. C., Taguchi, T., Testa, J. R., Hamilton, T. C. Identification of a gene containing zinc-finger motifs based on lost expression in malignantly transformed rat ovarian surface epithelial cells. Cancer Res. 57: 2029-2034, 1997. [PubMed: 9158001]
Abdollahi, A., Roberts, D., Godwin, A. K., Schultz, D. C., Sonoda, G., Testa, J. R., Hamilton, T. C. Identification of a zinc-finger gene at 6q25: a chromosomal region implicated in development of many solid tumors. Oncogene 14: 1973-1979, 1997. [PubMed: 9150364] [Full Text: https://doi.org/10.1038/sj.onc.1201034]
Arima, T., Drewell, R. A., Arney, K. L., Inoue, J., Makita, Y., Hata, A., Oshimura, M., Wake, N., Surani, M. A. A conserved imprinting control region at the HYMAI/ZAC domain is implicated in transient neonatal diabetes mellitus. Hum. Molec. Genet. 10: 1475-1483, 2001. [PubMed: 11448939] [Full Text: https://doi.org/10.1093/hmg/10.14.1475]
Arima, T., Yamasaki, K., John, R. M., Kato, K., Sakumi, K., Nakabeppu, Y., Wake, N., Kono, T. The human HYMAI/PLAGL1 differentially methylated region acts as an imprint control region in mice. Genomics 88: 650-658, 2006. [PubMed: 16928428] [Full Text: https://doi.org/10.1016/j.ygeno.2006.07.005]
Bilanges, B., Varrault, A., Mazumdar, A., Pantaloni, C., Hoffmann, A., Bockaert, J., Spengler, D., Journot, L. Alternative splicing of the imprinted candidate tumour suppressor gene ZAC regulates its antiproliferative and DNA binding activities. Oncogene 20: 1246-1253, 2001. [PubMed: 11313869] [Full Text: https://doi.org/10.1038/sj.onc.1204237]
Kamiya, M., Judson, H., Okazaki, Y., Kusakabe, M., Muramatsu, M., Takada, S., Takagi, N., Arima, T., Wake, N., Kamimura, K., Satomura, K., Hermann, R., Bonthron, D. T., Hayashizaki, Y. The cell cycle control gene ZAC/PLAGL1 is imprinted: a strong candidate gene for transient neonatal diabetes. Hum. Molec. Genet. 9: 453-460, 2000. [PubMed: 10655556] [Full Text: https://doi.org/10.1093/hmg/9.3.453]
Mackay, D. J. G., Coupe, A.-M., Shield, J. P. H., Storr, J. N. P., Temple, I. K., Robinson, D. O. Relaxation of imprinted expression of ZAC and HYMAI in a patient with transient neonatal diabetes mellitus. Hum. Genet. 110: 139-144, 2002. [PubMed: 11935319] [Full Text: https://doi.org/10.1007/s00439-001-0671-5]
Spengler, D., Villalba, M., Hoffmann, A., Pantaloni, C., Houssami, S., Bockaert, J., Journot, L. Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain. EMBO J. 16: 2814-2825, 1997. [PubMed: 9184226] [Full Text: https://doi.org/10.1093/emboj/16.10.2814]
Temple, I. K., Gardner, R. J., Robinson, D. O., Kibirige, M. S., Ferguson, A. W., Baum, J. D., Barber, J. C. K., James, R. S., Shield, J. P. H. Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22-q23. Hum. Molec. Genet. 5: 1117-1124, 1996. [PubMed: 8842729] [Full Text: https://doi.org/10.1093/hmg/5.8.1117]
Temple, I. K., James, R. S., Crolla, J. A., Sitch, F. L., Jacobs, P. A., Howell, W. M., Betts, P., Baum, J. D., Shield, J. P. H. An imprinted gene(s) for diabetes? (Letter) Nature Genet. 9: 110-112, 1995. [PubMed: 7719335] [Full Text: https://doi.org/10.1038/ng0295-110]
Valleley, E. M., Cordery, S. F., Bonthron, D. T. Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters. Hum. Molec. Genet. 16: 972-981, 2007. [PubMed: 17341487] [Full Text: https://doi.org/10.1093/hmg/ddm041]
Varrault, A., Ciani, E., Apiou, F., Bilanges, B., Hoffmann, A., Pantaloni, C., Bockaert, J., Spengler, D., Journot, L. hZAC encodes a zinc finger protein with antiproliferative properties and maps to a chromosomal region frequently lost in cancer. Proc. Nat. Acad. Sci. 95: 8835-8840, 1998. [PubMed: 9671765] [Full Text: https://doi.org/10.1073/pnas.95.15.8835]
Varrault, A., Gueydan, C., Delalbre, A., Bellmann, A., Houssami, S., Aknin, C., Severac, D., Chotard, L., Kahli, M., Le Digarcher, A., Pavlidis, P., Journot, L. Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth. Dev. Cell 11: 711-722, 2006. [PubMed: 17084362] [Full Text: https://doi.org/10.1016/j.devcel.2006.09.003]