Human Molecular Genetics, 2001, Vol. 10, No. 17 1721-1728
© 2001 Oxford University Press
Divergent evolution in M6P/IGF2R imprinting from the Jurassic to the Quaternary
Departments of Radiation Oncology and Pathology, Duke University Medical Center, Durham, NC 27710, USA, 1Department of Zoology, University College Dublin, Ireland and 2Medical Service and GRECC, VA Palo Alto Health Care System and Department of Medicine, Stanford University School of Medicine, Palo Alto, CA 94304, USA
Received April 16, 2001; Revised and Accepted June 19, 2001.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSACKNOWLEDGMENTSREFERENCES |
|---|
M6P/IGF2R imprinting first appeared approximately 150 million years ago following the divergence of prototherian from therian mammals. Although M6P/IGF2R is clearly imprinted in opossums and rodents, its imprint status in humans remains ambiguous. It is also still unknown if M6P/IGF2R imprinting was an ancestral mammalian epigenotype or if it evolved convergently. We report herein that M6P/IGF2R is imprinted in Artiodactyla, as it is in Rodentia and Marsupialia, but that it is not imprinted in Scandentia, Dermoptera and Primates, including ringtail lemurs and humans. These results are most parsimonious with a single ancestral origin of M6P/IGF2R imprinting followed by a lineage-specific disappearance of M6P/IGF2R imprinting in Euarchonta. The absence of M6P/IGF2R imprinting in extant primates, due to its disappearance from the primate lineage over 75 million years ago, demonstrates that imprinting at this locus does not predispose to human disease. Moreover, the divergent evolution of M6P/IGF2R imprinting predicts that the success of in vitro embryo procedures such as cloning may be species dependent.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSACKNOWLEDGMENTSREFERENCES |
|---|
M6P/IGF2R encodes for a multifunctional protein involved in lysosomal enzyme trafficking, fetal organogenesis, tumor suppression and T-cell mediated immunity (1–7). The essential role of M6P/IGF2R in gestational fetal growth control is evidenced by gene knock-out models in mice (2–4,8), as well as fetal overgrowth in sheep attributable to gene underexpression (9). Parentally imprinted M6P/IGF2R alleles invaded the ancestral mammalian gene pool over 100 million years ago, resulting in the expression of the maternally-inherited allele only (10). M6P/IGF2R imprinting evolved concurrently with receptor acquisition of an IGF2 binding site which is present in marsupials and eutherians, but not in amphibians, avians and monotremes (10–15). Thus, genetic and epigenetic modifications of M6P/IGF2R directed at controlling offspring growth occurred in therian mammals following their divergence from prototherians.
Although M6P/IGF2R is known to be imprinted in opossums and rodents (10,16,17), its imprint status in other mammals is uncertain. Humans were initially reported to differ from rodents by expressing both parental M6P/IGF2R alleles (18,19); however, subsequent studies provided evidence that M6P/IGF2R imprinting is a polymorphic trait in humans (20–22). The involvement of this receptor in fetal organogenesis, cellular growth suppression and T-cell mediated programmed cell death predicts that those individuals who inherit an imprinted M6P/IGF2R would be predisposed to fetal overgrowth, teratogenesis and carcinogenesis because of gene haploinsufficiency. It is therefore important to resolve the issue of whether the M6P/IGF2R is imprinted in the human population.
In this investigation the phylogenetic breadth of M6P/IGF2R imprinting in eutherian mammals was explored outside the superordinal clade that includes rodents and primates. We report herein that M6P/IGF2R is imprinted in the artiodactyls (i.e. sheep, cows and pigs), as it is in opossums (10) and rodents (16,23,24). In contrast, M6P/IGF2R imprinting is absent in all members of the Euarchonta clade, a taxonomic grouping that includes Scandentia (i.e. tree shrew), Dermoptera (i.e. colugo/‘flying lemur’) and Primates (i.e. ringtail lemur and humans). An ancestral origin followed by a more recent lineage-restricted loss of M6P/IGF2R imprinting is most parsimonious with this phylogenetic distribution. Since M6P/IGF2R imprinting disappeared in the primate lineage over 75 million years ago, and is totally absent in extant primates, imprinting at this locus does not predispose to human pathology. The defined evolutionary divergence of M6P/IGF2R imprinting during development also predicts that the success of in vitro embryo manipulations such as cloning may in part be species dependent.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSACKNOWLEDGMENTSREFERENCES |
|---|
M6P/IGF2R imprinting analysis in Artiodactyla
The sheep M6P/IGF2R ortholog was cloned and sequenced. Comparison of RT–PCR transcript sequences from 10 individual fetuses uncovered single nucleotide polymorphisms (SNPs) in exons 19 and 22 of the coding sequence (Table 1). RT–PCR amplimers containing these SNPs demonstrated monoallelic M6P/IGF2R expression in 5/5 heterozygous informative fetuses (Fig. 1A). Genotyping of parents demonstrated that the expressed allele is of maternal origin. Amplification of exon 48 and the 3'-untranslated region (3'-UTR) from cow and pig genomic DNA revealed the presence of three cow and two pig SNPs in exon 48 (Table 1). RT–PCR amplimers containing SNPs from fetal cows (Fig. 1B) and pigs (Fig. 1C) consistently revealed monoallelic M6P/IGF2R expression.
|
|
T transversion (arrow, fetus DNA) (sequenced in reverse direction). RNA analysis of this tissue demonstrates exclusive expression of the T allele (arrow, fetus cDNA) (sequenced in reverse direction). The maternal genotype is G/T (arrow, dam DNA) (sequenced in reverse direction) and the paternal genotype is G/G (arrow, sire DNA) (sequenced in reverse direction), demonstrating that the expressed T allele in the fetus is inherited from the mother. (B) The allelic expression of M6P/IGF2R in cows was determined using fetal liver tissue heterozygous for a c.8672AM6P/IGF2R imprinting analysis in Scandentia, Dermoptera and Prosimians
RT–PCR amplification of
3 kb of tree shrew and ringtail lemur M6P/IGF2R cDNA revealed several SNPs in each species (Table 1). Tree shrew and ringtail lemur fetal tissue were unavailable because of the scarcity of these protected species; however, tissues were obtained from animals that died perinatally. RT–PCR amplification of RNA isolated from tree shrew liver (Fig. 2A), and brain, heart, kidney, liver, lung, muscle and spleen tissues from ringtail lemurs (Fig. 2B) demonstrated equal transcription from both parental alleles. Kidney, liver and spleen were also obtained from five informative adult ringtail lemurs, and all tissues demonstrated biallelic M6P/IGF2R transcription (data not shown). Heart tissue from a single adult colugo also manifested biallelic M6P/IGF2R expression (data not shown).
|
M6P/IGF2R imprinting analysis in humans
There is difficulty in interpreting the results from the often used dinucleotide repeat and insertion/deletion polymorphisms in the 3'-UTR of human M6P/IGF2R (25,26). The results of expression analyses based on these polymorphisms are potentially misleading. Technical difficulties associated with the use of these polymorphisms (27), and the potential use of differential polyadenylation signals compromise a clear interpretation of the results obtained. Therefore, we utilized six SNPs within the coding sequence of the human M6P/IGF2R (27) in addition to the 3'-UTR tetranucleotide insertion/deletion polymorphism (26) to investigate M6P/IGF2R imprinting in humans. M6P/IGF2R imprinting was studied in a number of tissues from 75 conceptuses (i.e. 40 first trimester and 35 second trimester conceptuses); 12 term placentas were also investigated. PCR amplification of genomic DNA demonstrated that 58% (7/12) of the placental samples and 61% (46/75) of the conceptuses were heterozygous for one or more of these polymorphisms. RT–PCR of these informative samples revealed biallelic expression, with no evidence of skewed allelic expression, in every informative human embryonic tissue studied, including those from the brain, kidney, heart, liver, lung and placenta. Representative results are shown for first trimester fetal kidney tissue using the six identified SNPs (Table 1 and Fig. 3A) and the tetranucleotide insertion/deletion polymorphism (Fig. 3B) (26).
|
The M6P/IGF2R imprinting status was also determined in pediatric Wilms’ tumors. PCR amplification of genomic DNA demonstrated that 58% (7/12) of Wilms’ tumors developed in patients heterozygous for one or more of the identified SNPs. RT–PCR of these informative tumor samples revealed biallelic M6P/IGF2R expression in all Wilms’ tumors studied (Fig. 4).
|
CpG analysis of M6P/IGF2R intron 2 in Euarchonta
M6P/IGF2R intron 2 was PCR amplified directly from tree shrew and ringtail lemur genomic DNA. The 7.3 kb tree shrew and 6.5 kb lemur amplimers were sequenced, and then analyzed for the presence of a CpG island motif by the CpGPlot bioinformatics software. The M6P/IGF2R in both the tree shrew (Fig. 5C) and ringtail lemur (Fig. 5B) lacks an intron 2 CpG island, whereas the homologous region in the human M6P/IGF2R (Fig. 5A) contains such a motif (28,29). Using bisulfite sequencing analysis, we screened for differential methylation within intron 2 of the ringtail lemur (Fig. 5B) and tree shrew (Fig. 5C) M6P/IGF2R. All CpG dinucleotides analyzed for both species were fully methylated (data not shown). Thus, there was no evidence of the hemi-methylation that is characteristic of differentially methylated regions (DMRs) associated with imprinted genes. The phylogenetic distributions of M6P/IGF2R imprinting, and of a differentially methylated CpG island in intron 2 are shown in Figure 6.
|
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSACKNOWLEDGMENTSREFERENCES |
|---|
It was initially reported that M6P/IGF2R was exceptional among imprinted genes in that allelic silencing was not conserved between rodents and humans (18,19); however, subsequent reports provided evidence that M6P/IGF2R imprinting is polymorphic within the human population (20–22). The recent discovery that both M6P/IGF2R and IGF2 are imprinted in marsupials indicates that imprinted alleles are often stable over an extended period of time once they invade the genome (10,30). Therefore, the possibility of human M6P/IGF2R imprinting in a subset of people is an enigma that needs to be resolved because the clinical implications of polymorphic imprinting of this cell growth suppressor are significant (31). In addition, the absence of imprinting in humans and other mammals would shrink the known phylogenetic breadth of M6P/IGF2R imprinting to marsupials and rodents, thereby increasing the probability of convergent evolution of imprinting in these species.
To address these important issues, we first determined the phylogenetic distribution of M6P/IGF2R imprinting in eutherian mammals. Artiodactyla was found to be an additional mammalian order in which members are imprinted at the M6P/IGF2R locus during development. The most parsimonious interpretation of the presence of M6P/IGF2R imprinting in marsupials, rodents and artiodactyls, three distantly-related mammalian orders, is that the ancestral therian mammalian set of imprinted genes included M6P/IGF2R.
We next determined the imprinting status of M6P/IGF2R in the closest extant relatives of primates, Scandentians (i.e. tree shrews) and Dermopterans (i.e. colugos), and the most distant primate relatives of hominoids, the Prosimians (i.e. ringtail lemurs). We observed equal expression from both parental alleles in the tree shrew, colugo and ringtail lemur. These findings indicate that M6P/IGF2R imprinting is not only absent in primates, but that this codominant parental expression extends to the close non-primate relatives. Thus, M6P/IGF2R imprinting was already absent in primate ancestors some 75 million years ago, a conservative estimate for the divergence of Euarchonta.
M6P/IGF2R is thus exceptional among analyzed imprinted loci in that imprinting of this gene is not highly conserved between the mammalian orders. This is in contrast to IGF2, where imprinting appears to be a universal trait among wild-type therian mammals (30,32,33). Therefore, these mammalian evolutionary investigations support the postulate that the combined effects of natural selection do not tolerate or favor M6P/IGF2R imprinting in primates and their close relatives.
It can be further inferred that if M6P/IGF2R imprinting is polymorphic in humans, ancestral imprinted alleles are still present in the human population, or else M6P/IGF2R imprinting is convergently re-emerging following its disappearance. To directly assess the imprint status of M6P/IGF2R in humans during development, we analyzed multiple tissues from 46 unrelated human conceptuses. This large number of samples could easily detect the presence of M6P/IGF2R imprinting if 25–50% of human conceptuses are imprinted at this locus, as previously reported (20,21,29). Our analysis also predominantly included first trimester fetuses, in which M6P/IGF2R imprinting was reportedly most evident. We observed unambiguous biallelic M6P/IGF2R expression in every informative fetus. Epigenetic allele silencing was likewise not found in Wilms’ tumors, in contrast to the results of previous investigators that concluded that polymorphic imprinting of M6P/IGF2R predisposed children to this juvenile tumor (21). Interestingly, there are also no clinically recognized human syndromes associated with monoallelic expression of M6P/IGF2R; this is incompatible with reports of nearly half of all conceptuses being imprinted at this locus during development (20,21). The totality of our results are therefore consistent with M6P/IGF2R imprinting not being a polymorphic epigenotype in the human population.
A plausible explanation for the discrepancy between our results and those reporting polymorphic imprinting of M6P/IGF2R (20–22) lies in the polymorphisms used for allelic analysis. All reported cases of imprinted M6P/IGF2R expression involved the use of distal 3'-UTR polymorphisms, and none of these results has been confirmed using SNPs within the coding sequence. These 3'-UTR polymorphisms can be particularly problematic for allelic analysis because of technical difficulties with PCR amplification (27). The potential use of allele-specific differential polyadenylation signals could also result in apparent monoallelic expression even when the coding region of the gene is expressed from both parental alleles. Tissue culture is also known to alter M6P/IGF2R expression (9,28). The SNPs and in vivo tissues used in this study circumvent these potential problems.
The murine M6P/IGF2R contains a 1.5 kb CpG island in intron 2 (DMR2) that is methylated in mouse oocytes but not in sperm, and was predicted to play a role in imprint inheritance (34–36). This postulate was supported by the demonstration that deletion of the DMR2 results in biallelic M6P/IGF2R expression in the mouse (8). Nevertheless, M6P/IGF2R is biallelically expressed in mouse brain even though DMR2 remains differentially methylated (37). The marsupial opossum M6P/IGF2R is also imprinted, as it is in rodents and artiodactyls, but intron 2 entirely lacks a CpG island or any differentially methylated CpG dinucleotide sequences. In contrast, we now provide evidence that the human M6P/IGF2R is not imprinted even though a differentially methylated CpG island is present in intron 2 (28,29). Other members of Euarchonta such as the tree shrew and ringtail lemur, however, lack both M6P/IGF2R imprinting and the presence of DMR2. Thus, the presence of a DMR in intron 2 of the M6P/IGF2R is neither indicative of nor specific for imprinting at this locus.
The absence of a DMR2 in lemur and tree shrew is most parsimonious with human and mouse DMR2 not being orthologous, and human DMR2 therefore not being a vestige of ancestral M6P/IGF2R imprinting. This idea is supported by the lack of sequence and organizational homology between human and mouse DMR2. Moreover, human DMR2 cannot represent a remnant of an ancestral imprinting motif since the imprinted marsupial M6P/IGF2R does not contain a DMR2 (10). These findings are consistent with DMR2 having evolved convergently in select eutherian mammals after the ancestral establishment of M6P/IGF2R imprinting, and also subsequent to the disappearance of M6P/IGF2R imprinting in Euarchonta. The existence of a DMR in intron 2 of the unimprinted human M6P/IGF2R indicates that such regions are not always associated with imprinted genes, and that they may be widespread in mammalian genomes and/or these elements are mobile. Further investigations of DMR distribution in the human genome are needed to resolve these issues.
The marked species difference in M6P/IGF2R imprinting between humans and the other viviparous mammals such as mice has important biological consequences. In accord with the Knudson two-hit model of tumor suppressor gene inactivation (38), only a single mutation is required to negate M6P/IGF2R tumor suppressor function in mice, since one allele is already inactivated by the epigenetic phenomenon of imprinting. In contrast, two mutational events are required to inactivate this gene in humans (31,39). The functional haploid state of M6P/IGF2R in mice, but not in humans, provides a plausible explanation of why mice are more susceptible to cancer than humans. It also brings into question the relevance of human carcinogen risk assessments that are based solely on mouse studies (40).
In vitro embryo culture and cloning of livestock often result in prenatal and perinatal lethality associated with large offspring syndrome (LOS). In sheep, LOS correlates with epigenetic changes in M6P/IGF2R and decreased gene expression (9). Our finding that M6P/IGF2R is in fact imprinted during sheep, pig and cow development indicates that livestock may be subject to reduced M6P/IGF2R expression through in vitro embryo manipulations that specifically alter epigenetic imprint programming thereby resulting in fetal overgrowth. Interestingly, human embryo development resulting from either in vitro fertilization or cloning may not be as adversely impacted by this problem since the M6P/IGF2R is not imprinted in humans. In support of this postulate, fetal overgrowth has not been reported to be a specific complication of human in vitro fertilization and embryo transfer procedures followed by gestational surrogacy (41).
The results of this study demonstrate a clear divergence of primates and their close relatives from artiodactyls, rodents and marsupials in M6P/IGF2R imprinting. They further show that DMR2 is poorly correlated with imprinting in therian mammals, thereby questioning the universal importance of this element in M6P/IGF2R imprint regulation. Thus, phylogenetic inference coupled with gene expression analysis provide evidence that male and female mammalian ancestors of humans resolved an epigenetic struggle at the M6P/IGF2R locus (42) that would otherwise have resulted in enhanced disease susceptibility and many more visits to the clinic.
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSACKNOWLEDGMENTSREFERENCES |
|---|
Tissue samples
Fetal sheep tissues from 10 individuals and respective parental blood samples were a kind gift of B.Freking (Clay Center, NE). Twenty-five fetal pigs from five different mothers and two fetal cow livers were obtained from Neese’s Sausage (Burlington, NC) and Martin’s Abattoir (Spivey’s Corner, NC), respectively. Tree shrew tissue was obtained from an animal that died perinatally at Duke University (Durham, NC). A colugo heart specimen preserved at –80°C was provided by the Field Museum of Natural History (Chicago, IL). Kidney, liver and spleen from five adult ringtail lemurs, and a complete ringtail lemur conceptus that died perinatally, were obtained from the frozen tissue archives of the Duke University Primate Center. The Obstetrics and Gynecology Department of Duke University Medical Center provided 12 human placenta samples from term deliveries. Tissues from 75 unrelated human conceptuses were obtained from the NIH funded Birth Defects Research Laboratory at the University of Washington (Seattle, WA). Wilms’ tumors from 12 different patients were obtained from the Duke Comprehensive Cancer Center frozen tissue bank facility.
Nucleic acid preparation
Genomic DNA and total RNA were extracted by homogenizing 100 mg of tissue in DNA-Stat 60 and RNA-Stat 60, respectively; the DNA and RNA were extracted according to the manufacturer’s protocol (Tel-Test, Friendswood, TX). cDNA was prepared by reverse transcription of 1–5 µg of total RNA using an oligo-dT primer (SuperScript II, Life Technologies).
M6P/IGF2R ortholog identification
Tree shrew (accession no. AF339161), colugo (accession no. AG339163), ringtail lemur (accession no. AF339160) and human (accession no. NM_000876) M6P/IGF2R cDNA sequences have been characterized previously. A partial M6P/IGF2R transcript (7 kb) from sheep (accession no. AF353513) was amplified and sequenced with the use of cross-species RT–PCR primers as described previously (10,43). Pig (accession no. AF342812) and cow (accession no. AF342811) 3'-UTR M6P/IGF2R sequence, not previously characterized, were obtained by a combination of EST database analysis and sequencing of 3'-RACE products (Roche Molecular Biochemicals, Indianapolis, IN).
Genomic imprint analysis
Imprinting was determined by comparing genomic PCR and RT–PCR amplimers of regions containing known SNPs (44). SNPs were identified directly in exon-spliced RT–PCR products of tree shrew, colugo, ringtail lemur and human M6P/IGF2R as sequence dimorphisms in ABI Prism sequence histograms (ABI 377 sequencer; PE Biosystems, Foster City, CA) since M6P/IGF2R expression is biallelic in these species. In contrast, sheep, pig, and cow M6P/IGF2R SNPs were identified by alignment of amplified and sequenced transcripts from multiple individual fetal liver cDNA preparations since this gene is monoallelically expressed in these species. All SNPs were confirmed by repeat PCR amplifications, and the sequencing of these products in both the forward and reverse directions. PCR primers were designed to amplify the genomic DNA surrounding each SNP used in this study. Monoallelic versus biallelic expression was determined by comparing the RT–PCR and genomic PCR amplimers at each polymorphic site. The ratios of maternal to paternal allelic band intensities in the DNA and cDNA were compared. Expression was considered to be biallelic if the DNA to cDNA allelic band intensity ratios were equal (i.e. allelic ratio of 0.7–1.3). The absence of genomic DNA in RT–PCR products was confirmed by amplimer size and by direct sequencing across spliced exon–exon junctions. SNP locations for human and non-human M6P/IGF2R orthologs are provided in Table 1. The PCR primers used to amplify the regions containing human SNPs have been described previously (27,45); the PCR primers for amplifying the non-human SNPs are available upon request. We analyzed a four-base insertion/deletion polymorphism (ACAA) in the 3'-UTR of human M6P/IGF2R (accession no. NM_000876, nucleotide position 8412–8415) (26) by PCR amplification using the forward primer p#2633 (5'-GTCAGTATTTTTGCCGGCTGGTGA-3'); and the reverse primer p#2634 (5'-ACACAAATCAATCTTTGGGCAGGTTG-3').
CpG analysis of M6P/IGF2R intron 2
M6P/IGF2R intron 2 sequences for chicken (accession no. AF305581), platypus (accession no. AF151171) and opossum (accession no. AF225877) have been characterized previously (10,32). The complete 18 kb human (accession no. AF348209) and 8.3 kb mouse (accession no. AF366566) M6P/IGF2R intron 2 were established from bacterial artificial chromosome sequences. The complete M6P/IGF2R intron 2 sequence for tree shrew (accession no. AF339164) and ringtail lemur (accession no. AY030099) were amplified from genomic DNA with PCR primers that hybridize in exons 2 and 3 (tree shrew forward primer int2F, 5'-CTCTGCGGAAACGTGGGCATTAC-3' and reverse primer int2R, 5'-CTGCAGCTCAGGGTTGTGTTGAATTC-3'; ringtail lemur forward primer int2F, 5'-GGGCCATCAAGTGCTGTCTGTATG-3' and reverse primer int2R, 5'-GTGTTGAATTCCAGAATAGATGTGGTTGTACTTCTC-3'). Amplimers were gel extracted and sequenced on an ABI Prism DNA sequencer. CpG island analysis was performed with CpGPlot (http://bioweb.pasteur.fr/seqanal/interfaces/cpgplot.html).
Methylation analysis using bisulfite sequencing
Genomic DNAs were treated with sodium bisulfite to convert all unmethylated cytosines to uracils, leaving methylated cytosines intact. Sodium bisulfite treatment was performed using the CpGenome DNA modification kit according to the manufacturer’s protocol (Intergen, NY). 200 ng of bisulfite-treated DNA was empirically determined to avoid stochastic PCR amplification bias due to a limiting number of starting DNA molecules, and was therefore used as template for PCR amplification. Primer sequences used for amplification of CpG-containing regions are available upon request from the authors. Bisulfite-treated DNA was amplified using one round of PCR (40 cycles of 95°C for 30 s, 55°C for 30 s and 72°C for 30 s), and sequenced using radiolabeled terminator cycle sequencing (USB Corporation, Cleveland, OH).
|
ACKNOWLEDGMENTS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSACKNOWLEDGMENTSREFERENCES |
|---|
The authors wish to thank the Duke University DNA analysis facility for DNA sequencing. This study was supported by NIH grants CA25951, DK36054 and ES08823, DOD grant DAMD17-98-1-8305, The Research Service of the Department of Veterans Affairs, Sumitomo Chemical Company and AstraZeneca Pharmaceuticals. For additional information on genomic imprinting visit http://www.geneimprint.com.
|
FOOTNOTES |
|---|
+ To whom correspondence should be addressed at: Duke University Medical Center, Box 3433, Durham, NC 27710, USA. Tel: +1 919 684 2770; Fax: +1 919 684 5584; Email: jirtle@radonc.duke.edu
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSACKNOWLEDGMENTSREFERENCES |
|---|
1 Kornfeld, S. (1992) Structure and function of the mannose 6-phosphate/insulin-like growth factor II receptors. Annu. Rev. Biochem., 61, 307–330.[Web of Science][Medline]
2 Wang, Z.Q., Fung, M.R., Barlow, D.P. and Wagner, E.F. (1994) Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene. Nature, 372, 464–467.[Medline]
3 Lau, M.M., Stewart, C.E., Liu, Z., Bhatt, H., Rotwein, P. and Stewart, C.L. (1994) Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. Genes Dev., 8, 2953–2963.
4 Ludwig, T., Eggenschwiler, J., Fisher, P., D’Ercole, A.J., Davenport, M.L. and Efstratiadis, A. (1996) Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. Dev. Biol., 177, 517–535.[Web of Science][Medline]
5 Melnick, M., Chen, H., Buckley, S., Warburton, D. and Jaskoll, T. (1998) Insulin-like growth factor II receptor, transforming growth factor-beta, and Cdk4 expression and the developmental epigenetics of mouse palate morphogenesis and dysmorphogenesis. Dev. Dyn., 211, 11–25.[Web of Science][Medline]
6 Jirtle, R.L. (1999) Mannose 6-phosphate receptors. In Creidton, T.E. (ed.), Encyclopedia of Molecular Biology. Wiley-Liss, Inc., New York, pp. 1441–1447.
7 Motyka, B., Korbutt, G., Pinkoski, M.J., Heibein, J.A., Caputo, A., Hobman, M., Barry, M., Shostak, I., Sawchuk, T., Holmes, C.F. et al. (2000) Mannose 6-phosphate/insulin-like growth factor II receptor is a death receptor for granzyme B during cytotoxic T cell-induced apoptosis. Cell, 103, 491–500.[Web of Science][Medline]
8 Wutz, A., Theussl, H.C., Dausman, J., Jaenisch, R., Barlow, D.P. and Wagner, E.F. (2001) Non-imprinted Igf2r expression decreases growth and rescues the Tme mutation in mice. Development, 128, 1881–1887.[Abstract]
9 Young, L.E., Fernandes, K., McEvoy, T.G., Butterwith, S.C., Gutierrez, C.G., Carolan, C., Broadbent, P.J., Robinson, J.J., Wilmut, I. and Sinclair, K.D. (2001) Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture. Nat. Genet., 27, 153–154.[Web of Science][Medline]
10 Killian, J.K., Byrd, J.C., Jirtle, J.V., Munday, B.L., Stoskopf, M.K., MacDonald, R.G. and Jirtle, R.L. (2000) M6P/IGF2R imprinting evolution in mammals. Mol. Cell, 5, 707–716.[Web of Science][Medline]
11 Morgan, D.O., Edman, J.C., Standring, D.N., Fried, V.A., Smith, M.C., Roth, R.A. and Rutter, W.J. (1987) Insulin-like growth factor II receptor as a multifunctional binding protein. Nature, 329, 301–307.[Medline]
12 MacDonald, R.G., Pfeffer, S.R., Coussens, L., Tepper, M.A., Brocklebank, C.M., Mole, J.E., Anderson, J.K., Chen, E., Czech, M.P. and Ullrich, A. (1988) A single receptor binds both insulin-like growth factor II and mannose-6-phosphate. Science, 239, 1134–1137.
13 Clairmont, K.B. and Czech, M.P. (1989) Chicken and Xenopus mannose 6-phosphate receptors fail to bind insulin-like growth factor II. J. Biol. Chem. 264, 16390–16392.
14 Dahms, N.M., Brzycki-Wessell, M.A., Ramanujam, K.S. and Seetharam, B. (1993) Characterization of mannose 6-phosphate receptors (MPRs) from opossum liver: opossum cation-independent MPR binds insulin-like growth factor-II. Endocrinology, 133, 440–446.
15 Yandell, C.A., Dunbar, A.J., Wheldrake, J.F. and Upton, Z. (1999) The kangaroo cation-independent mannose 6-phosphate receptor binds insulin-like growth factor II with low affinity. J. Biol. Chem., 274, 27076–27082.
16 Barlow, D.P., Stöger, R., Herrmann, B.G., Saito, K. and Schweifer, N. (1991) The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature, 349, 84–87.[Medline]
17 Mills, J.J., Falls, J.G., De Souza, A.T. and Jirtle, R.L. (1998) Imprinted M6p/Igf2 receptor is mutated in rat liver tumors. Oncogene, 16, 2797–2802.[Web of Science][Medline]
18 Kalscheuer, V.M., Mariman, E.C., Schepens, M.T., Rehder, H. and Ropers, H.-H. (1993) The insulin-like growth factor type-2 receptor gene is imprinted in the mouse but not in humans. Nat. Genet., 5, 74–78.[Web of Science][Medline]
19 Ogawa, O., McNoe, L.A., Eccles, M.R., Morison, I.M. and Reeve, A.E. (1993) Human insulin-like growth factor type I and type II receptors are not imprinted. Hum. Mol. Genet., 2, 2163–2165.
20 Xu, Y., Goodyer, C.G., Deal, C. and Polychronakos, C. (1993) Functional polymorphism in the parental imprinting of the human IGF2R gene. Biochem. Biophys. Res. Commun., 197, 747–754.[Web of Science][Medline]
21 Xu, Y.Q., Grundy, P. and Polychronakos, C. (1997) Aberrant imprinting of the insulin-like growth factor II receptor gene in Wilms’ tumor. Oncogene, 14, 1041–1046.[Web of Science][Medline]
22 Oudejans, C.B., Westerman, B., Wouters, D., Gooyer, S., Leegwater, P.A., van Wijk, I.J. and Sleutels, F. (2001) Allelic Igf2r repression does not correlate with expression of antisense RNA in human extraembryonic tissues. Genomics, 73, 331–337.[Web of Science][Medline]
23 Mills, J.J., Jirtle, R.L. and Boyer, I.J. (1995) Mechanisms of liver tumor promotion. In Jirtle, R.L. (ed.), Liver Regeneration and Carcinogenesis: Molecular and Cellular Mechanisms. Academic Press, San Diego, pp. 199–226.
24 Vrana, P.B., Guan, X.J., Ingram, R.S. and Tilghman, S.M. (1998) Genomic imprinting is disrupted in interspecific Peromyscus hybrids. Nat. Genet., 20, 362–365.[Web of Science][Medline]
25 Goto, J., Figlewicz, D.A., Marineau, C., Khodr, N. and Rouleau, G.A. (1992) Dinucleotide repeat polymorphism at the IGF2R locus. Nucleic Acids Res., 20, 923.
26 Hol, F.A., Geurds, M.P., Hamel, B.C. and Mariman, E.C. (1992) Improving the polymorphism content of the 3'-UTR of the human IGF2R gene. Hum. Mol. Genet., 1, 347.
27 Killian, J.K., Oka, Y., Jang, H.-S., Fu, X., Sohda, T., Sakaguchi, S. and Jirtle, R.L. (2001) Mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) variants in American and Japanese populations. Hum. Mutat., 18, 25–31.[Web of Science][Medline]
28 Smrzka, O.W., Fae, I., Stoger, R., Kurzbauer, R., Fischer, G.F., Henn, T., Weith, A. and Barlow, D.P. (1995) Conservation of a maternal-specific methylation signal at the human IGF2R locus. Hum. Mol. Genet., 4, 1945–1952.
29 Wutz, A., Smrzka, O.W. and Barlow, D.P. (1998) Making sense of imprinting the mouse and human IGF2R loci. Novartis Found. Symp., 214, 251–259.[Medline]
30 O’Neill, M.J., Ingram, R.S., Vrana, P.B. and Tilghman, S.M. (2000) Allelic expression of IGF2 in marsupials and birds. Dev. Genes Evol., 210, 18–20.[Web of Science][Medline]
31 Jirtle, R.L. (1999) Genomic imprinting and cancer. Exp. Cell Res., 248, 18–24.[Web of Science][Medline]
32 Nolan, C.M., Killian, J.K., Petitte, J.N. and Jirtle, R.L. (2001) Imprint status of M6P/IGF2R and IGF2 in chickens. Dev. Genes Evol., 211, 179–183.[Web of Science][Medline]
33 Killian, J.K., Nolan, C.M., Stewart, N., Munday, B.L., Andersen, N.A., Nicol, S. and Jirtle, R.L. (2001) Monotreme IGF2 expression and ancestral origin of genomic imprinting. J. Exp. Zool., 291, 205–212.[Web of Science][Medline]
34 Stöger, R., Kubicka, P., Liu, C.G., Kafri, T., Razin, A., Cedar, H. and Barlow, D.P. (1993) Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal. Cell, 73, 61–71.[Web of Science][Medline]
35 Wutz, A., Smrzka, O.W., Schweifer, N., Schellander, K., Wagner, E.F. and Barlow, D.P. (1997) Imprinted expression of the Igf2r gene depends on an intronic CpG island. Nature, 389, 745–749.[Medline]
36 Birger, Y., Shemer, R., Perk, J. and Razin, A. (1999) The imprinting box of the mouse Igf2r gene. Nature, 397, 84–88.[Medline]
37 Hu, J.F., Oruganti, H., Vu, T.H. and Hoffman, A.R. (1998) Tissue-specific imprinting of the mouse insulin-like growth factor II receptor gene correlates with differential allele-specific DNA methylation. Mol. Endocrinol., 12, 220–232.
38 Knudson, A.G., Jr. (1971) Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA, 68, 820–823.
39 Pulford, D.J., Falls, J.G., Killian, J.K. and Jirtle, R.L. (1999) Polymorphisms, genomic imprinting and cancer susceptibility. Mutat. Res., 436, 59–67.[Web of Science][Medline]
40 Murphy, S.K. and Jirtle, R.L. (2000) Imprinted genes as potential genetic and epigenetic toxicologic targets. Environ. Health Perspect., 108 (Suppl. 1), 5–11.
41 Koudstaal, J., Braat, D.D., Bruinse, H.W., Naaktgeboren, N., Vermeiden, J.P. and Visser, G.H. (2000) Obstetric outcome of singleton pregnancies after IVF: a matched control study in four Dutch university hospitals. Hum. Reprod., 15, 1819–1825.
42 Haig, D. and Graham, C. (1991) Genomic imprinting and the strange case of the insulin-like growth factor II receptor. Cell, 64, 1045–1046.[Web of Science][Medline]
43 Killian, J.K., Buckley, T.R., Stewart, N., Munday, B.L. and Jirtle, R.L. (2001) Marsupials and eutherians reunited: genetic evidence for the theria hypothesis of mammalian evolution. Mamm. Genome, 12, 513–517.[Web of Science][Medline]
44 Kelsey, G. and Reik, W. (1998) Analysis and identification of imprinted genes. Methods, 14, 211–234.[Web of Science][Medline]
45 Killian, J.K. and Jirtle, R.L. (1999) Genomic structure of the human M6P/IGF2 receptor. Mamm. Genome, 10, 74–77.[Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. R. Bischoff, S. Tsai, N. Hardison, A. A. Motsinger-Reif, B. A. Freking, D. Nonneman, G. Rohrer, and J. A. Piedrahita Characterization of Conserved and Nonconserved Imprinted Genes in Swine Biol Reprod, November 1, 2009; 81(5): 906 - 920. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Niemann, X C. Tian, W A. King, and R. S F Lee Epigenetic reprogramming in embryonic and foetal development upon somatic cell nuclear transfer cloning Reproduction, February 1, 2008; 135(2): 151 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Thurston, J. Taylor, J. Gardner, K. D Sinclair, and L. E Young Monoallelic expression of nine imprinted genes in the sheep embryo occurs after the blastocyst stage Reproduction, January 1, 2008; 135(1): 29 - 40. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Price, S. K. Murphy, and E. V. Younglai Perspectives: The Possible Influence of Assisted Reproductive Technologies on Transgenerational Reproductive Effects of Environmental Endocrine Disruptors Toxicol. Sci., April 1, 2007; 96(2): 218 - 226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Johnstone, A. J. DuBose, C. R. Futtner, M. D. Elmore, C. I. Brannan, and J. L. Resnick A human imprinting centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for Angelman syndrome imprinting defects Hum. Mol. Genet., February 1, 2006; 15(3): 393 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Huang, Y. Wen, R. Shandilya, J. R. Marks, A. Berchuck, and S. K. Murphy High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer Nucleic Acids Res., January 23, 2006; 34(2): 555 - 563. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Pauler, S. H. Stricker, K. E. Warczok, and D. P. Barlow Long-range DNase I hypersensitivity mapping reveals the imprinted Igf2r and Air promoters share cis-regulatory elements Genome Res., October 1, 2005; 15(10): 1379 - 1387. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. P. Luedi, A. J. Hartemink, and R. L. Jirtle Genome-wide prediction of imprinted murine genes Genome Res., June 1, 2005; 15(6): 875 - 884. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P V Gordon, J B Paxton, and N S Fox The cellular repressor of E1A-stimulated genes mediates glucocorticoid-induced loss of the type-2 IGF receptor in ileal epithelial cells J. Endocrinol., May 1, 2005; 185(2): 265 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. O'Neill The influence of non-coding RNAs on allele-specific gene expression in mammals Hum. Mol. Genet., April 15, 2005; 14(suppl_1): R113 - R120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. H. Vu, T. Li, and A. R. Hoffman Promoter-restricted histone code, not the differentially methylated DNA regions or antisense transcripts, marks the imprinting status of IGF2R in human and mouse Hum. Mol. Genet., October 1, 2004; 13(19): 2233 - 2245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Beaujean, J. E. Taylor, M. McGarry, J. O. Gardner, I. Wilmut, P. Loi, G. Ptak, C. Galli, G. Lazzari, A. Bird, et al. The effect of interspecific oocytes on demethylation of sperm DNA PNAS, May 18, 2004; 101(20): 7636 - 7640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. T. Ruddock, K. J. Wilson, M. A. Cooney, N. A. Korfiatis, R. T. Tecirlioglu, and A. J. French Analysis of Imprinted Messenger RNA Expression During Bovine Preimplantation Development Biol Reprod, April 1, 2004; 70(4): 1131 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. BRAIDOTTI, T. BAUBEC, F. PAULER, C. SEIDL, O. SMRZKA, S. STRICKER, I. YOTOVA, and D.P. BARLOW The Air Noncoding RNA: An Imprinted cis-silencing Transcript Cold Spring Harb Symp Quant Biol, January 1, 2004; 69(0): 55 - 66. [Abstract] [PDF]
|
|
|
|
 |
|
 Evolution of Imprinted Tumor Susceptibility Genes: RANDY L. JIRTLE, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710 Toxicol Pathol, January 1, 2004; 32(1): 136 - 137. [PDF]
|
|
|
|
 |
|
 C Gicquel, J Weiss, J Amiel, V Gaston, Y Le Bouc, and C D Scott Epigenetic abnormalities of the mannose-6-phosphate/IGF2 receptor gene are uncommon in human overgrowth syndromes J. Med. Genet., January 1, 2004; 41(1): e4 - 4. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Yang, T. Li, T. H. Vu, G. A. Ulaner, J.-F. Hu, and A. R. Hoffman The Histone Code Regulating Expression of the Imprinted Mouse Igf2r Gene Endocrinology, December 1, 2003; 144(12): 5658 - 5670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Arnaud, D. Monk, M. Hitchins, E. Gordon, W. Dean, C. V. Beechey, J. Peters, W. Craigen, M. Preece, P. Stanier, et al. Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark Hum. Mol. Genet., May 1, 2003; 12(9): 1005 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Dinc Ethical Issues Regarding Human Cloning: a nursing perspective Nursing Ethics, May 1, 2003; 10(3): 238 - 254. [Abstract] [PDF]
|
|
|
|
|
|
L Bentley, K Nakabayashi, D Monk, C Beechey, J Peters, Z Birjandi, F E Khayat, M Patel, M A Preece, P Stanier, et al. The imprinted region on human chromosome 7q32 extends to the carboxypeptidase A gene cluster: an imprinted candidate for Silver-Russell syndrome J. Med. Genet., April 1, 2003; 40(4): 249 - 256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Wylie, D. J. Pulford, A. J. McVie-Wylie, R. A. Waterland, H. K. Evans, Y.-T. Chen, C. M. Nolan, T. C. Orton, and R. L. Jirtle Tissue-Specific Inactivation of Murine M6P/IGF2R Am. J. Pathol., January 1, 2003; 162(1): 321 - 328. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. De Rycke, I. Liebaers, and A. Van Steirteghem Epigenetic risks related to assisted reproductive technologies: Risk analysis and epigenetic inheritance Hum. Reprod., October 1, 2002; 17(10): 2487 - 2494. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||