Alternative titles; symbols
HGNC Approved Gene Symbol: MEST
Cytogenetic location: 7q32.2 Genomic coordinates (GRCh38): 7:130,486,175-130,506,465 (from NCBI)
The MEST gene is imprinted and expressed only from the paternal allele. It encodes a protein with significant amino acid homology to enzymes of the alpha/beta hydrolase fold family that is most strongly expressed during embryogenesis (summary by Kobayashi et al., 2001).
Genetic and embryologic studies in the mouse demonstrate functional differences between parental chromosomes during development. These differences result from imprinted genes whose expression is dependent on parental origin. In a systematic screen for imprinted genes, Kaneko-Ishino et al. (1995) identified and isolated a gene they designated Peg1 (paternally expressed gene-1). Peg1 is not expressed in parthenogenones. In interspecific hybrids, only the paternal copy of the gene is expressed in the individual tissues of embryos, neonates, and adults. Sado et al. (1993) isolated this gene in the mouse and termed it mesoderm-specific transcript (Mest) because it was predominantly expressed in mesoderm and its derivatives. See also Peg3 (601483).
Nishita et al. (1996) isolated a human homolog of Mest and showed that it shares about 70% nucleotide sequence homology with the mouse gene. Southern blot analysis showed that the MEST gene is expressed in all major fetal organs and tissues, which does not contradict the mesoderm-specific expression. The predicted 335-amino acid human MEST has a potential N-linked glycosylation site and has 97.3% amino acid similarity with its mouse counterpart. MEST was abundantly expressed in hydatidiform moles of androgenetic origin, whereas it was barely detectable in dermoid cysts of parthenogenetic origin. Thus it seems likely that the MEST gene is maternally repressed (imprinted), as is the mouse homolog.
Riesewijk et al. (1997) isolated a cDNA encoding MEST from a fetal cDNA library. The human MEST protein shares 98% amino acid identity with the mouse sequence. By SSCP and sequence analysis, followed by RT-PCR, Riesewijk et al. (1997) showed that tissues from 4 heterozygous fetuses all displayed monoallelic paternal expression, whereas lymphocytes from heterozygous adults showed biallelic expression. Methylation analysis indicated that maternal but not paternal fetal and adult tissue CpG islands are completely methylated in the promoter region, suggesting that an alternate promoter might be used in adult lymphocytes.
Using a conserved 16-amino acid motif found in epoxide hydrolase-related enzymes to query a human protein database, Decker et al. (2012) identified a 335-amino acid MEST isoform. The MEST protein has a predicted N-terminal transmembrane anchor, and the remainder of the molecule forms an epoxide hydrolase alpha/beta fold domain with a central lid region.
MEST Intronic Transcript 1
Nakabayashi et al. (2002) used RT-PCR and somatic cell hybrids containing a paternal or maternal human chromosome 7 in order to screen for imprinted genes. The authors identified a 4.2-kb transcript which they named MESTIT1 (for MEST intronic transcript-1) which was paternally (and not maternally) expressed in all fetal tissues and fibroblasts examined. MESTIT1 was located in an intron of 1 of the 2 isoforms of MEST but was transcribed in the opposite direction. The transcript was composed of at least 2 exons without any significant open reading frame (ORF). The authors suggested that MESTIT1 is a paternally expressed noncoding RNA that may be involved in the regulation of MEST expression during development.
Lefebvre et al. (1997) detected partial methylation of the CpG island spanning exon 1 of the Peg1 gene in day 13.5 postcoitum mouse embryos and undifferentiated embryonic stem cells. Using embryos carrying a targeted mutation at the Peg1 locus, Lefebvre et al. (1997) showed that this partial promoter methylation pattern reflects a strict parent-of-origin-specific differential methylation: the expressed paternal allele is unmethylated, whereas the silenced maternal allele is fully methylated at the CpG site studied. Using analysis of DNA isolated from sperm and parthenogenetic embryos, Lefebvre et al. (1997) also demonstrated that the gametes carry the epigenetic information necessary to lay down this allele-specific methylation pattern.
Kosaki et al. (2000) demonstrated that (1) an alternative isoform of MEST is expressed concurrently with the original isoform in adult lymphocytes and lymphoblastoid cell lines, and (2) isoform-1 (the original isoform) is expressed only from the paternal allele, whereas isoform-2 (the alternative isoform) is expressed from both the paternal allele and the maternal allele. These results were discordant with the results of previous studies, which supported biallelic expression of the MEST gene in lymphocytes. As shown by MEST and by GNAS1 (139320), nonimprinted or reciprocally imprinted isoforms may be expressed in tissues in which imprinting is apparently lost. The authors stated that isoform-2 of Mest may not be expressed in mouse peripheral blood and/or lymphocytes. Kosaki et al. (2000) concluded that human MEST is imprinted in an isoform-specific manner rather than in a tissue-specific manner in lymphocytes.
Riesewijk et al. (1997) determined that the MEST gene spans approximately 13 kb.
Lefebvre et al. (1997) described the genomic structure of Peg1 as well as the DNA sequence of the 5-prime end of the gene, including 2.4 kb of promoter sequences and covering the first 2 exons. They identified a CpG island spanning exon 1 and G-rich repeats within intron 1.
Riesewijk et al. (1998) determined the complete genomic structure of the MEST gene, which comprises 12 exons.
Nishita et al. (1996) mapped the MEST gene to 7q32 by fluorescence in situ hybridization Kobayashi et al. (1997) demonstrated that PEG1/MEST is an imprinted gene expressed from a paternal allele and is located on 7q31-q32, near D7S649. For the mapping, Kobayashi et al. (1997) identified 4 independent YAC clones containing the PEG1/MEST gene by screening the CEPH YAC library.
The Mest gene maps to an imprinted region of mouse chromosome 6 and is expressed monoallelically from the paternal allele. When the null allele is paternally transmitted, the offspring exhibits severe intrauterine growth retardation. Uniparental disomy of mouse chromosome 6 is associated with a similar phenotype, presumably as a result of lack of expression of the Mest gene (Ferguson-Smith et al., 1991). The human homolog, MEST, maps to 7q31.3, within a region of conserved synteny corresponding to mouse chromosome 6, and is monoallelically expressed from the paternal allele in a wide variety of tissues during prenatal and postnatal development. Uniparental disomy of chromosome 7 in humans is associated with phenotypic features of Silver-Russell syndrome (SRS2; 618905), a heterogeneous disorder characterized by intrauterine and postnatal growth retardation, with or without additional dysmorphic features. Kotzot et al. (1995) predicted the presence of at least one maternally repressed gene on human chromosome 7, because they found maternal uniparental disomy for this chromosome in 4 of 35 patients with SRS. Nishita et al. (1996) suggested that MEST, the first imprinted gene to be identified on chromosome 7, is involved in the causation of this syndrome. Riesewijk et al. (1998) performed a mutation screen of the PEG1/MEST gene in 49 patients with SRS and 9 patients with primordial growth retardation (PGR). Apart from 1 silent mutation and 2 novel polymorphisms, nucleotide changes were not detected in any of the SRS or PGR patients. Moreover, methylation patterns of the 5-prime region of PEG1/MEST were found to be normal in 35 SRS and 9 PGR patients and different from the pattern seen in patients with maternal uniparental disomy 7.
Kobayashi et al. (2001) presented findings indicating that PEG1/MEST can be excluded as a major determinant of SRS. In a screening of 15 SRS patients, no aberrant expression patterns of 2 splice variants were detected in lymphocytes. Direct sequence analysis failed to detect any mutations in the coding region of isoform-1, which the authors called alpha, and there were no significant mutations in the 5-prime flanking upstream region containing the predicted promoter and the genomic region that is highly conserved between human and mouse. Differential methylation patterns of the CpG islands for the alpha isoform were normally maintained and resulted in the same patterns as in normal controls, suggesting that there was no loss of imprinting.
Based on the differential methylation of the promoter region of the imprinted PEG1/MEST locus on 7q32, Moore et al. (2003) designed a multiplex methylation PCR assay to rapidly distinguish uniparental disomy of chromosome 7 (UPD7) from biparental inheritance of chromosome 7. The advantage of this assay is that parental samples are not required and that amplification of both alleles in the same reaction is simpler and provides an internal control. The authors suggested that the method could be used in screening for UPD7 in patients with Silver-Russell syndrome, for example.
To study the role of Mest during development, Lefebvre et al. (1998) disrupted the gene by gene targeting in embryonic stem (ES) cells. They found that the targeted mutation was imprinted and reversibly silenced by passage through the female germline. Paternal transmission activated the targeted allele and caused embryonic growth retardation associated with reduced postnatal survival rates in mutant progeny. Significantly, Mest-deficient females showed abnormal maternal behavior and impaired placentophagia, a distinctive mammalian behavior. The results provided evidence for the involvement of an imprinted gene in the control of adult behavior. Lefebvre et al. (1998) noted Mest +/- females delivered at term, with a normal pregnancy rate, but produced few, if any, surviving progeny. Mest function appears to be required for the appropriate immediate response of females to their pups. In light of the importance of olfactory cues in maternal behavior and of the expression of Mest in the olfactory bulb, Mest +/- females were tested for olfactory function; no olfactory defect could be demonstrated, however.
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Kobayashi, S., Kohda, T., Miyoshi, N., Kuroiwa, Y., Aisaka, K., Tsutsumi, O., Kaneko-Ishino, T., Ishino, F. Human PEG1/MEST, an imprinted gene on chromosome 7. Hum. Molec. Genet. 6: 781-786, 1997. [PubMed: 9158153] [Full Text: https://doi.org/10.1093/hmg/6.5.781]
Kobayashi, S., Uemura, H., Kohda, T., Nagai, T., Chinen, Y., Naritomi, K., Kinoshita, E., Ohashi, H., Imaizumi, K., Tsukahara, M., Sugio, Y., Tonoki, H., Kishino, T., Tanaka, T., Yamada, M., Tsutsumi, O., Niikawa, N., Kaneko-Ishino, T., Ishino, F. No evidence of PEG1/MEST gene mutations in Silver-Russell syndrome patients. Am. J. Med. Genet. 104: 225-231, 2001. [PubMed: 11754049]
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Moore, M. W., Dietz, L. G., Tirtorahardjo, B., Cotter, P. D. A multiplex methylation PCR assay for identification of uniparental disomy of chromosome 7. Hum. Mutat. 21: 645-648, 2003. [PubMed: 12754712] [Full Text: https://doi.org/10.1002/humu.10222]
Nakabayashi, K., Bentley, L., Hitchins, M. P., Mitsuya, K., Meguro, M., Minagawa, S., Bamforth, J. S., Stanier, P., Preece, M., Weksberg, R., Oshimura, M., Moore, G. E., Scherer, S. W. Identification and characterization of an imprinted antisense RNA (MESTIT1) in the human MEST locus on chromosome 7q32. Hum. Molec. Genet. 11: 1743-1756, 2002. [PubMed: 12095916] [Full Text: https://doi.org/10.1093/hmg/11.15.1743]
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Riesewijk, A. M., Blagitko, N., Schinzel, A. A., Hu, L., Schulz, U., Hamel, B. C. J., Ropers, H.-H., Kalscheuer, V. M. Evidence against a major role of PEG1/MEST Silver-Russell syndrome. Europ. J. Hum. Genet. 6: 114-120, 1998. [PubMed: 9781054] [Full Text: https://doi.org/10.1038/sj.ejhg.5200164]
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