Abstract
As the ‘gateway’ to the fetus, the placenta is subject to a myriad of environmental factors, each with the potential to alter placental epigenetic and gene expression profile. This can have direct consequences for the developing fetus and potentially even long-term health implications. As a result, interest in placental epigenetics generally, and changes occurring in placenta-associated disease, has intensified over recent years. This article will discuss the general features of placental DNA methylation and will describe current technologies for profiling genome-wide DNA methylation patterns in this tissue, the approaches to data analysis and some of the major findings from recent studies.
Papers of special note have been highlighted as: ▪ of interest
Bibliography
- 1 De Witt F: An historical study on theories of the placenta to 1900. J. Hist. Med. Allied Sci.14,360–374 (1959).
- 2 Huppertz B: The anatomy of the normal placenta. J. Clin. Pathol.61(12),1296–1302 (2008).
- 3 Benerischke K, Kaufmann P: Pathology of the Human Placenta (6th Edition). Springer, Germany (2006).
- 4 Evain-Brion D, Malassine A: Human placenta as an endocrine organ. Growth Horm. IGF Res.13(Suppl. A),S34–S37 (2003).
- 5 Barker DJ: The developmental origins of insulin resistance. Horm. Res.64(Suppl. 3),2–7 (2005).
- 6 Gottesman II, Hanson DR: Human development: biological and genetic processes. Annu. Rev. Psychol.56,263–286 (2005).
- 7 Hanson MA, Gluckman PD: Developmental processes and the induction of cardiovascular function: conceptual aspects. J. Physiol.565(Pt 1),27–34 (2005).
- 8 Sood R, Zehnder JL, Druzin ML, Brown PO: Gene expression patterns in human placenta. Proc. Natl Acad. Sci. USA103(14),5478–5483 (2006).
- 9 Rawn SM, Cross JC: The evolution, regulation, and function of placenta-specific genes. Annu. Rev. Cell Dev. Biol.24,159–181 (2008).
- 10 Lambertini L, Diplas AI, Lee MJ, Sperling R, Chen J, Wetmur J: A sensitive functional assay reveals frequent loss of genomic imprinting in human placenta. Epigenetics3(5),261–269 (2008).
- 11 Coan PM, Burton GJ, Ferguson-Smith AC: Imprinted genes in the placenta--a review. Placenta26(Suppl. A),S10–S20 (2005).
- 12 Frost JM, Moore GE: The importance of imprinting in the human placenta. PLoS Genet.6,e1001015 (2010).
- 13 Wagschal A, Feil R: Genomic imprinting in the placenta. Cytogenet. Genome Res.113(1–4),90–98 (2006).
- 14 Ng HK, Novakovic B, Hiendleder S, Craig JM, Roberts CT, Saffery R: Distinct patterns of gene-specific methylation in mammalian placentas: implications for placental evolution and function. Placenta31(4),259–268 (2010).
- 15 Monk M, Boubelik M, Lehnert S: Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development99(3),371–382 (1987).
- 16 Jirtle RL, Skinner MK: Environmental epigenomics and disease susceptibility. Nat. Rev. Genet.8(4),253–262 (2007).
- 17 Okada Y, Yamagata K, Hong K, Wakayama T, Zhang Y: A role for the elongator complex in zygotic paternal genome demethylation. Nature463(7280),554–558 (2010).
- 18 Chapman V, Forrester L, Sanford J, Hastie N, Rossant J: Cell lineage-specific undermethylation of mouse repetitive DNA. Nature307(5948),284–286 (1984).
- 19 Razin A, Webb C, Szyf M et al.: Variations in DNA methylation during mouse cell differentiation in vivo and in vitro. Proc. Natl Acad. Sci. USA81(8),2275–2279 (1984).
- 20 Santos F, Hendrich B, Reik W, Dean W: Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev. Biol.241(1),172–182 (2002).
- 21 Gama-Sosa MA, Wang RY, Kuo KC, Gehrke CW, Ehrlich M: The 5-methylcytosine content of highly repeated sequences in human DNA. Nucleic Acids Res.11(10),3087–3095 (1983).
- 22 Gama-Sosa MA, Slagel VA, Trewyn RW et al.: The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res.11(19),6883–6894 (1983).
- 23 Tsien F, Fiala ES, Youn B et al.: Prolonged culture of normal chorionic villus cells yields ICF syndrome-like chromatin decondensation and rearrangements. Cytogenet. Genome Res.98(1),13–21 (2002).
- 24 Reiss D, Zhang Y, Mager DL: Widely variable endogenous retroviral methylation levels in human placenta. Nucleic Acids Res.35(14),4743–4754 (2007).
- 25 Shen HM, Nakamura A, Sugimoto J et al.: Tissue specificity of methylation and expression of human genes coding for neuropeptides and their receptors, and of a human endogenous retrovirus K family. J. Hum. Genet.51(5),440–450 (2006).
- 26 Medstrand P, Landry JR, Mager DL: Long terminal repeats are used as alternative promoters for the endothelin B receptor and apolipoprotein C-I genes in humans. J. Biol. Chem.276(3),1896–1903 (2001).
- 27 Gimenez J, Montgiraud C, Pichon JP et al.: Custom human endogenous retroviruses dedicated microarray identifies self-induced HERV-W family elements reactivated in testicular cancer upon methylation control. Nucleic Acids Res.38(7),2229–2246 (2009).
- 28 Cotton AM, Avila L, Penaherrera MS, Affleck JG, Robinson WP, Brown CJ: Inactive X chromosome-specific reduction in placental DNA methylation. Hum. Mol. Genet.18(19),3544–3552 (2009).▪ Reported lower methylation on the inactive X chromosome in placenta compared with whole blood. This finding sheds light on the relationship between DNA methylation and X inactivation in different cell types.
- 29 Zaragoza MV, Surti U, Redline RW, Millie E, Chakravarti A, Hassold TJ: Parental origin and phenotype of triploidy in spontaneous abortions: predominance of diandry and association with the partial hydatidiform mole. Am. J. Hum. Genet.66(6),1807–1820 (2000).
- 30 Perrin D, Ballestar E, Fraga MF et al.: Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta. Oncogene26(17),2518–2524 (2007).
- 31 Monk D, Arnaud P, Apostolidou S et al.: Limited evolutionary conservation of imprinting in the human placenta. Proc. Natl Acad. Sci. USA103(17),6623–6628 (2006).
- 32 Renfree MB, Hore TA, Shaw G, Graves JA, Pask AJ: Evolution of genomic imprinting: insights from marsupials and monotremes. Annu. Rev. Genomics Hum. Genet.10,241–262 (2009).
- 33 Pozharny Y, Lambertini L, Ma Y et al.: Genomic loss of imprinting in first-trimester human placenta. Am. J. Obstet. Gynecol.202(4),391.e391–e398 (2010).
- 34 McMinn J, Wei M, Sadovsky Y, Thaker HM, Tycko B: Imprinting of PEG1/MEST isoform 2 in human placenta. Placenta27(2–3),119–126 (2006).
- 35 Diplas AI, Lambertini L, Lee MJ et al.: Differential expression of imprinted genes in normal and IUGR human placentas. Epigenetics4(4),235–240 (2009).
- 36 Bourque DK, Avila L, Penaherrera M, von Dadelszen P, Robinson WP: Decreased placental methylation at the H19/IGF2 imprinting control region is associated with normotensive intrauterine growth restriction but not preeclampsia. Placenta31(3),197–202 (2010).
- 37 Guo L, Choufani S, Ferreira J et al.: Altered gene expression and methylation of the human chromosome 11 imprinted region in small for gestational age (SGA) placentae. Dev. Biol.320(1),79–91 (2008).
- 38 Tabano S, Colapietro P, Cetin I et al.: Epigenetic modulation of the IGF2/H19 imprinted domain in human embryonic and extra-embryonic compartments and its possible role in fetal growth restriction. Epigenetics5(4),313–324 (2010).
- 39 Mann MR, Lee SS, Doherty AS et al.: Selective loss of imprinting in the placenta following preimplantation development in culture. Development131(15),3727–3735 (2004).
- 40 Zechner U, Pliushch G, Schneider E et al.: Quantitative methylation analysis of developmentally important genes in human pregnancy losses after ART and spontaneous conception. Mol. Hum. Reprod.16(9),704–713 (2009).
- 41 Haycock PC, Ramsay M: Exposure of mouse embryos to ethanol during preimplantation development: effect on DNA methylation in the h19 imprinting control region. Biol. Reprod.81(4),618–627 (2009).
- 42 Luo YM, Fang Q, Zhuang GL, Liang RC, Liu QL: [Characteristics of IGF-II gene imprinting in twin placentas]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi23(5),497–501 (2006).
- 43 Chiu RW, Chim SS, Wong IH et al.: Hypermethylation of RASSF1A in human and rhesus placentas. Am. J. Pathol.170(3),941–950 (2007).
- 44 Guilleret I, Osterheld MC, Braunschweig R, Gastineau V, Taillens S, Benhattar J: Imprinting of tumor-suppressor genes in human placenta. Epigenetics4(1),62–68 (2009).
- 45 Novakovic B, Rakyan V, Ng HK et al.: Specific tumour-associated methylation in normal human term placenta and first-trimester cytotrophoblasts. Mol. Hum. Reprod.14(9),547–554 (2008).
- 46 Wong NC, Novakovic B, Weinrich B et al.: Methylation of the adenomatous polyposis coli (APC) gene in human placenta and hypermethylation in choriocarcinoma cells. Cancer Lett.268(1),56–62 (2008).
- 47 Xue WC, Feng HC, Tsao SW et al.: Methylation status and expression of E-cadherin and cadherin-11 in gestational trophoblastic diseases. Int. J. Gynecol. Cancer13(6),879–888 (2003).
- 48 Novakovic B, Sibson M, Ng HK et al.: Placenta-specific methylation of the vitamin D 24-hydroxylase gene: implications for feedback autoregulation of active vitamin D levels at the fetomaternal interface. J. Biol. Chem.284(22),14838–14848 (2009).
- 49 Novakovic B, Wong NC, Sibson M et al.: DNA methylation-mediated down-regulation of DNA methyltransferase-1 (DNMT1) is coincident with, but not essential for, global hypomethylation in human placenta. J. Biol. Chem.285(13),9583–9593 (2010).
- 50 Chim SS, Tong YK, Chiu RW et al.: Detection of the placental epigenetic signature of the maspin gene in maternal plasma. Proc. Natl Acad. Sci. USA102(41),14753–14758 (2005).
- 51 Bellido ML, Radpour R, Lapaire O et al.: MALDI-TOF mass array analysis of RASSF1A, SERPINB5 methylation patterns in human placenta and plasma. Biol. Reprod.82(4),745–750 (2010).
- 52 Zhang HJ, Siu MK, Wong ES et al.: Oct4 is epigenetically regulated by methylation in normal placenta and gestational trophoblastic disease. Placenta29(6),549–554 (2008).
- 53 Bellido ML, Radpour R, Lapaire O et al.: MALDI-TOF Mass array analysis of RASSF1A, SERPINB5 methylation patterns in human placenta and plasma. Biol. Reprod.745–750 (2010).
- 54 Bourque DK, Avila L, Penaherrera M, von Dadelszen P, Robinson WP: Decreased Placental Methylation at the H19/IGF2 imprinting control region is associated with normotensive intrauterine growth restriction but not preeclampsia. Placenta31(3),197–202 (2010).
- 55 Brown L, Brown G, Vacek P, Brown S: Aneuploidy detection in mixed DNA samples by methylation-sensitive amplification and microarray analysis. Clin. Chem.56(5),805–813 (2010).
- 56 Chu T, Burke B, Bunce K, Surti U, Allen Hogge W, Peters DG: A microarray-based approach for the identification of epigenetic biomarkers for the noninvasive diagnosis of fetal disease. Prenat. Diagn.29(11),1020–1030 (2009).▪ Using a high resolution 215,060 probe custom oligonucleotide microarray for chromosomes 13, 18 and 21, this study identified over 6000 potential biomarkers for fetal aneuploidy in maternal plasma.
- 57 Papageorgiou EA, Fiegler H, Rakyan V et al.: Sites of differential DNA methylation between placenta and peripheral blood: molecular markers for noninvasive prenatal diagnosis of aneuploidies. Am. J. Pathol.174(5),1609–1618 (2009).▪ Using a high-resolution tiling array for chromosomes 21, 13, 18, X and Y, this study found that most DNA methylation differences between first- and third-trimester placenta and maternal blood occur in nongenic regions.
- 58 Tong YK, Jin S, Chiu RW et al.: Noninvasive prenatal detection of trisomy 21 by an epigenetic-genetic chromosome-dosage approach. Clin. Chem.56(1),90–98 (2010).
- 59 Laird PW: Principles and challenges of genome-wide DNA methylation analysis. Nat. Rev. Genet.11(3),191–203 (2010).▪ Up-to-date review of next-generation sequencing technology, with a focus on data analysis approaches and future directions in the field.
- 60 Metzker ML: Sequencing technologies – the next generation. Nat. Rev. Genet.11(1),31–46 (2010).
- 61 Rakyan V, Down T, Thorne N et al.: An integrated resource for genome-wide identification and analysis of human tissue-specific differentially methylated regions (tDMRs). Genome Res.18(9),1518–1529 (2008).▪ Useful resource of DNA methylation patterns in several human tissue types, including placenta.
- 62 Christensen BC, Houseman EA, Marsit CJ et al.: Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet.5(8),e1000602 (2009).
- 63 Houseman EA, Christensen BC, Yeh RF et al.: Model-based clustering of DNA methylation array data: a recursive-partitioning algorithm for high-dimensional data arising as a mixture of β distributions. BMC Bioinformatics9,365 (2008).
- 64 Yuen RK, Avila L, Penaherrera MS et al.: Human placental-specific epipolymorphism and its association with adverse pregnancy outcomes. PLoS One4(10),e7389 (2009).▪ This study used the GoldenGate 1536 probe array to study variable DNA methylation loci, ‘epipolymorphisms’, in placentas from unrelated individuals. Almost 10% of probes showed high variation between 13 unrelated placentas.
- 65 Jinno Y, Yun K, Nishiwaki K et al.: Mosaic and polymorphic imprinting of the WT1 gene in humans. Nat. Genet.6(3),305–309 (1994).
- 66 Tzschoppe AA, Struwe E, Dorr HG et al.: Differences in gene expression dependent on sampling site in placental tissue of fetuses with intrauterine growth restriction. Placenta31(3),178–185 (2009).
- 67 Gicquel C, Gaston V, Mandelbaum J, Siffroi JP, Flahault A, Le Bouc Y: In vitro fertilization may increase the risk of Beckwith–Wiedemann syndrome related to the abnormal imprinting of the KCN1OT gene. Am. J. Hum. Genet.72(5),1338–1341 (2003).
- 68 Orstavik KH, Eiklid K, van der Hagen CB et al.: Another case of imprinting defect in a girl with Angelman syndrome who was conceived by intracytoplasmic semen injection. Am. J. Hum. Genet.72(1),218–219 (2003).
- 69 Allen C, Bowdin S, Harrison RF et al.: Pregnancy and perinatal outcomes after assisted reproduction: a comparative study. Ir. J. Med. Sci.177(3),233–241 (2008).
- 70 Bowdin S, Allen C, Kirby G et al.: A survey of assisted reproductive technology births and imprinting disorders. Hum. Reprod.22(12),3237–3240 (2007).
- 71 Cox GF, Burger J, Lip V et al.: Intracytoplasmic sperm injection may increase the risk of imprinting defects. Am. J. Hum. Genet.71(1),162–164 (2002).
- 72 DeBaun MR, Niemitz EL, Feinberg AP: Association of in vitro fertilization with Beckwith-Wiedemann syndrome and epigenetic alterations of LIT1 and H19. Am. J. Hum. Genet.72(1),156–160 (2003).
- 73 Fauque P, Jouannet P, Lesaffre C et al.: Assisted reproductive technology affects developmental kinetics, h19 imprinting control region methylation and h19 gene expression in individual mouse embryos. BMC Dev. Biol.7,116 (2007).
- 74 Gomes MV, Huber J, Ferriani RA, Amaral Neto AM, Ramos ES: Abnormal methylation at the KvDMR1 imprinting control region in clinically normal children conceived by assisted reproductive technologies. Mol. Hum. Reprod.15(8),471–477 (2009).
- 75 Halliday J, Oke K, Breheny S, Algar E, J Amor D: Beckwith–Wiedemann syndrome and IVF: a case-control study. Am. J. Hum. Genet.75(3),526–528 (2004).
- 76 Kallen B, Finnstrom O, Nygren KG, Olausson PO: In vitro fertilization (IVF) in Sweden: infant outcome after different IVF fertilization methods. Fertil. Steril.84(3),611–617 (2005).
- 77 Kallen B, Finnstrom O, Nygren KG, Olausson PO: In vitro fertilization (IVF) in Sweden: risk for congenital malformations after different IVF methods. Birth Defects Res. A Clin. Mol. Teratol.73(3),162–169 (2005).
- 78 Lidegaard O, Pinborg A, Andersen AN: Imprinting diseases and IVF: Danish National IVF cohort study. Hum. Reprod.20(4),950–954 (2005).
- 79 Lim D, Bowdin SC, Tee L et al.: Clinical and molecular genetic features of Beckwith-Wiedemann syndrome associated with assisted reproductive technologies. Hum. Reprod.24(3),741–747 (2009).
- 80 Maher ER, Brueton LA, Bowdin SC et al.: Beckwith-Wiedemann syndrome and assisted reproduction technology (ART). J. Med. Genet.40(1),62–64 (2003).
- 81 Pinborg A, Lidegaard O, Andersen AN: The vanishing twin: a major determinant of infant outcome in IVF singleton births. Br. J. Hosp. Med. (Lond.)67(8),417–420 (2006).
- 82 Pinborg A, Lidegaard O, Freiesleben NC, Andersen AN: Vanishing twins: a predictor of small-for-gestational age in IVF singletons. Hum. Reprod.22(10),2707–2714 (2007).
- 83 Pinborg A, Lidegaard O, la Cour Freiesleben N, Andersen AN: Consequences of vanishing twins in IVF/ICSI pregnancies. Hum. Reprod.20(10),2821–2829 (2005).
- 84 Rossignol S, Steunou V, Chalas C et al.: The epigenetic imprinting defect of patients with Beckwith-Wiedemann syndrome born after assisted reproductive technology is not restricted to the 11p15 region. J. Med. Genet.43(12),902–907 (2006).
- 85 Sato A, Otsu E, Negishi H, Utsunomiya T, Arima T: Aberrant DNA methylation of imprinted loci in superovulated oocytes. Hum. Reprod.22(1),26–35 (2007).
- 86 Shi W, Haaf T: Aberrant methylation patterns at the two-cell stage as an indicator of early developmental failure. Mol. Reprod. Dev.63(3),329–334 (2002).
- 87 Sutcliffe AG, Peters CJ, Bowdin S et al.: Assisted reproductive therapies and imprinting disorders – a preliminary British survey. Hum. Reprod.21(4),1009–1011 (2006).
- 88 Tierling S, Souren NY, Gries J et al.: Assisted reproductive technologies do not enhance the variability of DNA methylation imprints in human. J. Med. Genet. (2009).
- 89 Katari S, Turan N, Bibikova M et al.: DNA methylation and gene expression differences in children conceived in vitro or in vivo. Hum. Mol. Genet.18(20),3769–3778 (2009).▪ First study to examine the effects of in vitro fertilization on genome-wide DNA methylation patterns at promoter regions in placenta and cord blood. A trend towards lower methylation was detected in placentas from in vitro fertilization individuals.
- 90 Market-Velker BA, Zhang L, Magri LS, Bonvissuto AC, Mann MR: Dual effects of superovulation: loss of maternal and paternal imprinted methylation in a dose-dependent manner. Hum. Mol. Genet.19(1),36–51 (2010).
- 91 Li T, Vu TH, Ulaner GA et al.: IVF results in de novo DNA methylation and histone methylation at an Igf2-H19 imprinting epigenetic switch. Mol. Hum. Reprod.11(9),631–640 (2005).
- 92 Fauque P, Ripoche MA, Tost J et al.: Modulation of imprinted gene network in placenta results in normal development of in vitro manipulated mouse embryos. Hum. Mol. Genet.19(9),1779–1790 (2010).
- 93 Turan N, Katari S, Gerson LF et al.: Inter- and intra-individual variation in allele-specific DNA methylation and gene expression in children conceived using assisted reproductive technology. PLoS Genet.6(7),e1001033 (2010).
- 94 Zhang Y, Cui Y, Zhou Z, Sha J, Li Y, Liu J: Altered global gene expressions of human placentae subjected to assisted reproductive technology treatments. Placenta31(4),251–258 (2010).
- 95 Yu L, Chen M, Zhao D et al.: The H19 gene imprinting in normal pregnancy and pre-eclampsia. Placenta30(5),443–447 (2009).
- 96 Redman CW, Sargent IL: Latest advances in understanding preeclampsia. Science308(5728),1592–1594 (2005).
- 97 Fisher SJ: The placental problem: linking abnormal cytotrophoblast differentiation to the maternal symptoms of preeclampsia. Reprod. Biol. Endocrinol.2,53 (2004).
- 98 Barker DJ: Intra-uterine programming of the adult cardiovascular system. Curr. Opin Nephrol. Hypertens.6(1),106–110 (1997).
- 99 Tsui DW, Chan KC, Chim SS et al.: Quantitative aberrations of hypermethylated RASSF1A gene sequences in maternal plasma in pre-eclampsia. Prenat. Diagn.27(13) 1212–1218 (2007).
- 100 Yuen RK, Penaherrera MS, von Dadelszen P, McFadden DE, Robinson WP: DNA methylation profiling of human placentas reveals promoter hypomethylation of multiple genes in early-onset preeclampsia. Eur. J. Hum. Genet.18(9),1006–1012 (2010).
- 101 Pang ZJ, Xing FQ: Expression profile of trophoblast invasion-associated genes in the pre-eclamptic placenta. Br. J. Biomed. Sci.60(2),97–101 (2003).
- 102 Lo YM, Tein MS, Lau TK et al.: Quantitative analysis of fetal DNA in maternal plasma and serum: implications for noninvasive prenatal diagnosis. Am. J. Hum. Genet.62(4),768–775 (1998).
- 103 Lo YM, Lau TK, Zhang J et al.: Increased fetal DNA concentrations in the plasma of pregnant women carrying fetuses with trisomy 21. Clin. Chem.45(10),1747–1751 (1999).
- 104 Litton C, Stone J, Eddleman K, Lee MJ: Noninvasive prenatal diagnosis: past, present, and future. Mt. Sinai J. Med.76(6),521–528 (2009).
- 105 Chim SS, Jin S, Lee TY et al.: Systematic search for placental DNA-methylation markers on chromosome 21: toward a maternal plasma-based epigenetic test for fetal trisomy 21. Clin. Chem.54(3),500–511 (2008).