Epigenetics and assisted reproductive technology: a call for investigation.

A surprising set of recent observations suggests a link between assisted reproductive technology (ART) and epigenetic errors--that is, errors involving information other than DNA sequence that is heritable during cell division. An apparent association with ART was found in registries of children with Beckwith-Wiedemann syndrome, Angelman syndrome, and retinoblastoma. Here, we review the epidemiology and molecular biology behind these studies and those of relevant model systems, and we highlight the need for investigation of two major questions: (1) large-scale case-control studies of ART outcomes, including long-term assessment of the incidence of birth defects and cancer, and (2) investigation of the relationship between epigenetic errors in both offspring and parents, the specific methods of ART used, and the underlying infertility diagnoses. In addition, the components of proprietary commercial media used in ART procedures must be fully and publicly disclosed, so that factors such as methionine content can be assessed, given the relationship in animal studies between methionine exposure and epigenetic changes.

[1]  A. Feinberg,et al.  The history of cancer epigenetics , 2004, Nature Reviews Cancer.

[2]  J. Van der Elst,et al.  Perinatal Outcome of Pregnancies After Assisted Reproduction: A Case–Control Study , 1997, Journal of Assisted Reproduction and Genetics.

[3]  B. Horsthemke,et al.  Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma , 1989, Human Genetics.

[4]  Y. Englert,et al.  A prospective longitudinal study of the physical, psychomotor, and intellectual development of singleton children up to 5 years who were conceived by intracytoplasmic sperm injection compared with children conceived spontaneously and by in vitro fertilization. , 2003, Fertility and sterility.

[5]  J. Biggers,et al.  Chemically defined media and the culture of mammalian preimplantation embryos: historical perspective and current issues. , 2003, Human reproduction update.

[6]  Y. Yamazaki,et al.  Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Gerberding,et al.  Assisted reproductive technology surveillance--United States, 2000. , 2003, Morbidity and mortality weekly report. Surveillance summaries.

[8]  Robert A. Waterland,et al.  Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation , 2003, Molecular and Cellular Biology.

[9]  M. Leppert,et al.  Familial aggregation of abnormal methylation of parental alleles at the IGF2/H19 and IGF2R differentially methylated regions. , 2003, Human molecular genetics.

[10]  Antoine Flahault,et al.  In vitro fertilization may increase the risk of Beckwith-Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. , 2003, American journal of human genetics.

[11]  A. Feinberg,et al.  Loss of IGF2 Imprinting: A Potential Marker of Colorectal Cancer Risk , 2003, Science.

[12]  Maarten Boers,et al.  Incidence of retinoblastoma in children born after in-vitro fertilisation , 2003, The Lancet.

[13]  W. Reik,et al.  Beckwith-Wiedemann syndrome and assisted reproduction technology (ART) , 2003, Journal of medical genetics.

[14]  Andrew P Feinberg,et al.  Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. , 2003, American journal of human genetics.

[15]  K. Buiting,et al.  Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic semen injection. , 2003, American journal of human genetics.

[16]  A. Shearn,et al.  The ubiquitin ligase Hyperplastic discs negatively regulates hedgehog and decapentaplegic expression by independent mechanisms , 2002, Development.

[17]  P. Soloway,et al.  Regional loss of imprinting and growth deficiency in mice with a targeted deletion of KvDMR1 , 2002, Nature Genetics.

[18]  M. Surani,et al.  Epigenetic reprogramming in mouse primordial germ cells , 2002, Mechanisms of Development.

[19]  A. D. den Ouden,et al.  Congenital malformations in 4224 children conceived after IVF. , 2002, Human reproduction.

[20]  Bai-Lin Wu,et al.  Intracytoplasmic sperm injection may increase the risk of imprinting defects. , 2002, American journal of human genetics.

[21]  D. O’Carroll,et al.  Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression , 2002, The EMBO journal.

[22]  E. Li,et al.  Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. , 2002, Development.

[23]  N. Ogonuki,et al.  Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. , 2002, Development.

[24]  J. Kurinczuk,et al.  The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. , 2002, The New England journal of medicine.

[25]  L. Schieve,et al.  Low and very low birth weight in infants conceived with use of assisted reproductive technology. , 2002, The New England journal of medicine.

[26]  Andrew P Feinberg,et al.  Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects. , 2002, American journal of human genetics.

[27]  Y. Obata,et al.  Maternal Primary Imprinting Is Established at a Specific Time for Each Gene throughout Oocyte Growth* , 2002, The Journal of Biological Chemistry.

[28]  Wendy Dean,et al.  Dynamic reprogramming of DNA methylation in the early mouse embryo. , 2002, Developmental biology.

[29]  T. Bestor,et al.  Dnmt3L and the Establishment of Maternal Genomic Imprints , 2001, Science.

[30]  Karl Mechtler,et al.  Loss of the Suv39h Histone Methyltransferases Impairs Mammalian Heterochromatin and Genome Stability , 2001, Cell.

[31]  L. Young.  Imprinting of genes and the Barker hypothesis. , 2001, Twin research : the official journal of the International Society for Twin Studies.

[32]  B. Tycko,et al.  Epigenetic heterogeneity at imprinted loci in normal populations. , 2001, Biochemical and biophysical research communications.

[33]  C. Glass,et al.  Defect of histone acetyltransferase activity of the nuclear transcriptional coactivator CBP in Rubinstein-Taybi syndrome. , 2001, Human molecular genetics.

[34]  K. Zhao,et al.  MECP2 truncating mutations cause histone H4 hyperacetylation in Rett syndrome. , 2001, Human molecular genetics.

[35]  W. Reik,et al.  Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes1 , 2001, Biology of reproduction.

[36]  J. J. Robinson,et al.  Epigenetic change in IGF2R is associated with fetal overgrowth after sheep embryo culture , 2001, Nature Genetics.

[37]  I. Wilmut,et al.  In-utero overgrowth in ruminants following embryo culture: lessons from mice and a warning to men. , 2000, Human reproduction.

[38]  M. Bartolomei,et al.  The H19 methylation imprint is erased and re-established differentially on the parental alleles during male germ cell development. , 2000, Human molecular genetics.

[39]  W Miller,et al.  Sequence and comparative analysis of the mouse 1-megabase region orthologous to the human 11p15 imprinted domain. , 2000, Genome research.

[40]  M. Meguro,et al.  Targeted disruption of the human LIT1 locus defines a putative imprinting control element playing an essential role in Beckwith-Wiedemann syndrome. , 2000, Human molecular genetics.

[41]  Y. Hayashizaki,et al.  The paternal methylation imprint of the mouse H19 locus is acquired in the gonocyte stage during foetal testis development , 2000, Genes to cells : devoted to molecular & cellular mechanisms.

[42]  M. Bartolomei,et al.  Differential Effects of Culture on Imprinted H19 Expression in the Preimplantation Mouse Embryo1 , 2000, Biology of reproduction.

[43]  D. Ledbetter,et al.  Somatic segregation errors predominantly contribute to the gain or loss of a paternal chromosome leading to uniparental disomy for chromosome 15 , 2000, Clinical genetics.

[44]  W. Reik,et al.  Active demethylation of the paternal genome in the mouse zygote , 2000, Current Biology.

[45]  D. Higgs,et al.  Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation , 2000, Nature Genetics.

[46]  J. Walter,et al.  Embryogenesis: Demethylation of the zygotic paternal genome , 2000, Nature.

[47]  C. Wijmenga,et al.  The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[48]  N. Tommerup,et al.  Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene , 1999, Nature.

[49]  C. Papadopoulos,et al.  Nanoelectronics: Growing Y-junction carbon nanotubes , 1999, Nature.

[50]  D. Haber,et al.  DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development , 1999, Cell.

[51]  H. Zoghbi,et al.  Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 , 1999, Nature Genetics.

[52]  A. Haeringen,et al.  Angelman syndrome: a review of clinical and genetic aspects , 1999, Clinical Neurology and Neurosurgery.

[53]  D. J. Driscoll,et al.  A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[54]  A. Feinberg,et al.  Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[55]  M. Bartolomei,et al.  Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2. , 1998, Genes & development.

[56]  I Wilmut,et al.  Large offspring syndrome in cattle and sheep. , 1998, Reviews of reproduction.

[57]  R. Kodell,et al.  Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[58]  S. Clark,et al.  Bisulfite sequencing in preimplantation embryos: DNA methylation profile of the upstream region of the mouse imprinted H19 gene. , 1998, Genomics.

[59]  M Plachot,et al.  Chromosome methylation patterns during mammalian preimplantation development. , 1998, Genes & development.

[60]  M. Nöthen,et al.  Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis. , 1998, American journal of human genetics.

[61]  C. Plass,et al.  A methylation imprint mark in the mouse imprinted gene Grf1/Cdc25Mm locus shares a common feature with the U2afbp-rs gene: an association with a short tandem repeat and a hypermethylated region. , 1998, Genomics.

[62]  W. Reik,et al.  Transactivation of Igf2 in a mouse model of Beckwith–Wiedemann syndrome , 1997, Nature.

[63]  W. Miller,et al.  Long human-mouse sequence alignments reveal novel regulatory elements: a reason to sequence the mouse genome. , 1997, Genome research.

[64]  T. Dryja,et al.  Hypermethylation in the retinoblastoma gene is associated with unilateral, sporadic retinoblastoma. , 1997, Cancer genetics and cytogenetics.

[65]  M. Bartolomei,et al.  A 5' 2-kilobase-pair region of the imprinted mouse H19 gene exhibits exclusive paternal methylation throughout development , 1997, Molecular and cellular biology.

[66]  R. Fanchin,et al.  [Follow-up of a cohort of 422 children aged from 6 to 13 and conceived by in vitro fertilization]. , 1997, Contraception, fertilite, sexualite.

[67]  B. Lieberman,et al.  Children conceived by in vitro fertilisation after fresh embryo transfer , 1997, Archives of disease in childhood. Fetal and neonatal edition.

[68]  R. Fanchin,et al.  Follow-up of a cohort of 422 children aged 6 to 13 years conceived by in vitro fertilization. , 1997, Fertility and sterility.

[69]  A. Feinberg,et al.  Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements , 1997, Nature Genetics.

[70]  Ping Fang,et al.  De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome , 1997, Nature Genetics.

[71]  M. Lalande,et al.  UBE3A/E6-AP mutations cause Angelman syndrome , 1996, Nature Genetics.

[72]  B. Howard,et al.  The Transcriptional Coactivators p300 and CBP Are Histone Acetyltransferases , 1996, Cell.

[73]  G. Elgar,et al.  Quality not quantity: the pufferfish genome. , 1996, Human molecular genetics.

[74]  K. Saunders,et al.  Growth and physical outcome of children conceived by in vitro fertilization. , 1996, Pediatrics.

[75]  C. Polychronakos,et al.  Polymorphic functional imprinting of the human IGF2 gene among individuals, in blood cells, is associated with H19 expression. , 1996, Biochemical and biophysical research communications.

[76]  A. Sutcliffe,et al.  Minor congenital anomalies, major congenital malformations and development in children conceived from cryopreserved embryos. , 1995, Human reproduction.

[77]  Bernhard Horsthemke,et al.  Inherited microdeletions in the Angelman and Prader–Willi syndromes define an imprinting centre on human chromosome 15 , 1995, Nature Genetics.

[78]  D. Higgs,et al.  Mutations in a putative global transcriptional regulator cause X-linked mental retardation with α-thalassemia (ATR-X syndrome) , 1995, Cell.

[79]  J. Catt.  Bovine embryo co‐culture. , 1994, Cell biology international.

[80]  E. Wagner,et al.  Regulation of embryonic growth and lysosomal targeting by the imprintedIgf2/Mpr gene , 1994, Nature.

[81]  M. Sauer.  Assisted reproductive technology , 2018 .

[82]  C. Sapienza,et al.  The genetics of retinoblastoma, revisited. , 1994, American journal of human genetics.

[83]  R. Frydman,et al.  Task force report on the outcome of pregnancies and children conceived by in vitro fertilization (France: 1987 to 1989). , 1994, Fertility and sterility.

[84]  L. Strong,et al.  Concordance between parental origin of chromosome 13q loss and chromosome 6p duplication in sporadic retinoblastoma. , 1994, American journal of human genetics.

[85]  C. Polychronakos,et al.  Functional polymorphism in the parental imprinting of the human IGF2R gene. , 1993, Biochemical and biophysical research communications.

[86]  M. Scheffner,et al.  The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53 , 1993, Cell.

[87]  F. Ledeist,et al.  An embryonic-like methylation pattern of classical satellite DNA is observed in ICF syndrome. , 1993, Human molecular genetics.

[88]  T. Sakai,et al.  CpG methylation inactivates the promoter activity of the human retinoblastoma tumor-suppressor gene. , 1993, Oncogene.

[89]  Rudolf Jaenisch,et al.  Targeted mutation of the DNA methyltransferase gene results in embryonic lethality , 1992, Cell.

[90]  A. Razin,et al.  Developmental pattern of gene-specific DNA methylation in the mouse embryo and germ line. , 1992, Genes & development.

[91]  E. Engel,et al.  Uniparental disomy, isodisomy, and imprinting: probable effects in man and strategies for their detection. , 1991, American journal of medical genetics.

[92]  W. Reik,et al.  Methylation levels of maternal and paternal genomes during preimplantation development. , 1991, Development.

[93]  V. Blanquet,et al.  Physical map around the retinoblastoma gene: possible genomic imprinting suggested by NruI digestion. , 1991, Genomics.

[94]  T. Dryja,et al.  Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. , 1991, American journal of human genetics.

[95]  M. Pembrey,et al.  Uniparental paternal disomy in Angelman's syndrome , 1991, The Lancet.

[96]  A. Efstratiadis,et al.  Parental imprinting of the mouse insulin-like growth factor II gene , 1991, Cell.

[97]  T. Moore,et al.  Genomic imprinting in mammalian development: a parental tug-of-war. , 1991, Trends in genetics : TIG.

[98]  D. Barlow,et al.  The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus , 1991, Nature.

[99]  I. Kjellmer,et al.  Pregnancy Complications and Short‐Term Follow‐Up of Infants Born After in Vitro Fertilization and Embryo Transfer (IVF/ET) , 1991, Acta obstetricia et gynecologica Scandinavica.

[100]  W. Benedict,et al.  Preferential retention of paternal alleles in human retinoblastoma: evidence for genomic imprinting. , 1990, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[101]  S. Latt,et al.  Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. , 1989, American journal of medical genetics.

[102]  G. Sahagian,et al.  Biochemical evidence that the type II insulin-like growth factor receptor is identical to the cation-independent mannose 6-phosphate receptor. , 1988, The Journal of biological chemistry.

[103]  V. Chapman,et al.  Undermethylation of structural gene sequences in extraembryonic lineages of the mouse. , 1986, Developmental biology.

[104]  B. Cattanach,et al.  Differential activity of maternally and paternally derived chromosome regions in mice , 1985, Nature.

[105]  D. Solter,et al.  Completion of mouse embryogenesis requires both the maternal and paternal genomes , 1984, Cell.

[106]  M. Surani,et al.  Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis , 1984, Nature.

[107]  C. Wylie.  Primordial germ cells , 1980, Nature.

[108]  Nan Faion T. Wu,et al.  The Beckwith-Wiedemann Syndrome , 1974, Clinical pediatrics.

[109]  H. Kalter,et al.  Congenital malformations. , 1961, The New England journal of medicine.