REVIEW URRENT C OPINION
Genomic imprinting: sensing the environment and driving the fetal growth Luca Lambertini a,b
Purpose of review Genomic imprinting is an epigenetically-driven phenomenon that responds to environmental stimuli to determine the fetal growth trajectory. This review aims at describing the transgenerational meaning of genomic imprinting while supporting the study of genomic imprinting in placenta for the determination of an important biomarker of chronic and developmental disorders in children as driven by the environment. Recent findings Recent work has shown that genomic imprinting reaches beyond the basic significance of an epigenetic mark regulating gene expression. Genomic imprinting has been theorized as the main determinant of epigenetic inheritance. Concomitantly, new studies in the field of molecular epidemiology became available that tie the fetal growth trajectory to genomic imprinting in response to environmental stimuli, making of genomic imprinting the driving force of the fetal growth. When carried out in placenta, the effector of the intrauterine environment as conveyed by the maternal exposure to the general life environment, the study of genomic imprinting may reveal critical information on alterations of the fetal growth trajectory. Summary The study of genomic imprinting profiles in placentas from birth cohorts of individuals exposed to different environmental stimuli can provide a new, much needed, tool for the elaboration of effective public health intervention plans for child health. Keywords environment, fetal growth trajectory, genomic imprinting, placenta
INTRODUCTION Genomic imprinting refers to the monoallelic expression of genes accordingly to the parent of origin. Currently, about 90 imprinted genes have been identified and validated in the human genome, while it is expected that some additional 100 genes are imprinted [1 ,2,3,4 ]. Imprinted genes thus represent a rather small subset of the protein-coding genome (1%), which is even smaller if we consider all the known transcripts (less than 0.5%). It has been theorized that genomic imprinting evolved coincidentally with placentation, and its origin is postulated by the ‘parental conflict’ theory, which proposes that genomic imprinting evolved to allow proper distribution of maternal resources to the developing embryo [5,6]. This theory hypothesizes that there is a ‘tug of war’ between the paternally expressed genes that promote fetal growth, and the maternally expressed genes that have the opposite effect in order to preserve maternal energies. Genomic imprinting alterations &
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have been found linked to many developmental disorders in children while concomitantly responding to environmental exposures [7 ]. The review aims at providing a quick overview of the molecular features of genomic imprinting while tying these same features to the determination of the fetal growth trajectory. Evidence will be then provided showing that the study of genomic imprinting alterations in correlation with environmental exposures and child health outcomes can effectively be conducted by investigating the &&
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Department of Preventive Medicine and bDepartment of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, USA Correspondence to Luca Lambertini, PhD, Assistant Professor, Departments of Preventive Medicine and Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, One Gustave L. Levi Place, Box 1057, New York, NY 10029, USA. Tel: +1 212 824 7076; e-mail: [email protected] Curr Opin Pediatr 2014, 26:237–242 DOI:10.1097/MOP.0000000000000072
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KEY POINTS
trajectory of the embryo within a dynamic process intended to generate a progeny that best adapts to the life milieu it will face at birth [13–15,16 ]. Genomic imprinting, however, escapes this embryo re-programming wave supporting the theory that hypothesizes that genomic imprinting is the determinant of the parental epigenetic inheritance [17 ,18,19 ]. This theory is further supported by the discovery that the imprinting status of several imprinted genes/clusters, unlike the vast majority of the epigenetic phenomena that are tissuespecific, is consistently maintained unchanged across tissues/organs [20 ]. Interestingly, the imprinting status of these same imprinted genes may still be detectable in tissues/organs in which the imprinted genes no longer behave as such, but are instead commonly biallelically expressed [21–23]. At the same time, changes in the imprinting status do not directly correlate with changes in gene expression levels [24,25]. Genomic imprinting is thus more likely to represent the inherited organization of the chromatin rather than specifically controlling the expression dosage of imprinted genes by acting on their allele-specific expression [17 ,20 ]. As one of the determinants of the epigenetic inheritance, genomic imprinting has the potential to modify the phenotype if altered during embryogenesis. Accordingly, imprinted genes can be classified into three categories based on their functional roles: (1) genes that control the allocation of maternal resources to the fetus; (2) genes that regulate metabolism in the early postnatal period; and (3) genes that prenatally determine the metabolism of developing metabolic organs such as the pancreas, muscle, fat cells, and the hypothalamus [26,27]. The timely expression of imprinted genes is fundamental for the correct embryo development [28]. Additionally, imprinted gene expression demonstrates low transcriptional noise, as shown in the placenta [24]. This finding is in agreement with the imprinted genes functional importance that, as shown for other such genes [29,30], once altered, can lead to prominent phenotypic changes [31,32] such as lethality [33,34] that may be further enhanced by the constitutional haploinsufficiency of imprinted genes [35]. Given its relative ‘insensitivity’ to the common environmental signals that naturally shape the growth of the embryo and the critical role it plays in the embryo development, genomic imprinting is perfectly positioned to become a powerful biomarker for the detection of disorders brought about by exposures to toxic environmental stimuli that can disrupt both the imprinting status and the imprinted gene expression. &
Genomic imprinting is a transgenerational epigenetic multifactorial phenomenon. Genomic imprinting is sensitive to toxic environmental stimuli. Genomic imprinting can predict several developmental disorders in children. Genomic imprinting is best studied in placenta.
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placenta, the effector of the intrauterine environment. The last part of this review will discuss some of the currently accessible literature that supports the use of imprinting profiling as marker of exposure to ‘toxic’ environmental stimuli leading to alteration of the fetal growth trajectory.
GENOMIC IMPRINTING FEATURES Genomic imprinting is probably the best example of how multiple epigenetic layers act together on determining the phenotype. It has in fact been shown that DNA methylation, histone coding and chromatin-modeling elements like long nonprotein-coding RNAs (lncRNAs), coordinately work in regulating the monoallelic expression of imprinted genes [8,9]. Imprinted genes are often found in clusters regulated by imprinting control regions (ICRs), but single imprinted genes under the control of ICR-like elements (ILEs) are not uncommon. ICRs and ILEs are DNA sequences that determine the imprinting status by carrying the DNA methylation and histone code on the allele that they contribute to silence by also binding transcription regulatory complexes assisted by lncRNAs, which are abundant between imprinted genes [10–12]. ICRs can control the allele-specific expression of imprinted gene clusters ranging from 2 to 9 genes. ICRs may be located several kilobase pairs away from a specific imprinted gene cluster, in noncoding genomic areas or in the promoter or gene body of other imprinted/not imprinted genes. ILEs, on the contrary, are invariably located within the promoter region of imprinted genes that are not clustered [12]. Genomic imprinting shows peculiar features when compared with the vast majority of the other epigenetic phenomena. At fertilization, the epigenetic set-up of the embryo is completely reset to capture the common environmental signals, as conveyed by the mother through the intrauterine environment, that naturally shape the growth 238
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GENOMIC IMPRINTING AND DISEASE A vast scientific literature exists that linked alterations of the imprinting status and imprinted gene expression with developmental outcomes as mainly of neural and metabolic origin [36 ]. Alterations of the imprinting status and imprinted gene expression have been linked to severe neurodevelopmental disorders spanning from Beckwith-Wiedemann [37,38], Silver-Russel [39,40], Prader-Willi [41,42], and Angelman [43,44] syndromes all the way to autism spectrum disorders (ASD) [45–47]. These findings form the basis of the ‘imbalanced brain theory’ that may explain, at least partially, the ASD and schizophrenia sexual dichotomies, in which the imbalance of paternally expressed genes in the limbic system to maternally expressed genes in the cerebral cortex, in either direction, leads to the conditions that are characteristics of these two disorders [45,48–50]. Additionally, the fact that imprinting marks are inherited strongly suggests that any imprinting alteration early in development is likely to be detectable in most tissues and to have wide-ranging effects [51]. Other studies showed that imprinted gene expression is altered in placentas from pregnancies with intrauterine growth restriction (IUGR) [24,25]. IUGR is a fairly common pregnancy outcome that has been linked to alterations of the intrauterine environment leading to shallow implantation of the placenta in the uterine wall, hypoxia, vascular lesions, and uteroplacental insufficiency [52–54]. Babies from IUGR pregnancies carry higher risks for the development of coronary heart disease, hypertension, hyperlipidemia, and diabetes mellitus in adulthood (Barker hypothesis [55,56]), but also obesity [57,58] and neurodevelopmental disorders [59,60]. Supporting their functional importance, expression levels of the tested imprinted genes were found very tightly regulated with a limited transcriptional noise. The imprinted gene expression profiling in IUGR identified down-regulated (CCDC86, ILK, NNAT, PEG10, PHLDA2) as well as up-regulated (CDKAL1, DHCR24, PLAGL1, ZNF331) genes. IUGR has also been shown to induce changes in the imprinting status of several imprinted genes (DLK1, H19, PLAGL1, SNRPN) [24,61] as measured by assessing their monoallelic expression. Concomitantly, imprinted gene expression correlates with infant neurobehavior at birth, pregnancy outcomes as fetal growth restriction, and with measures of fetal development like head circumference and birth weight [62 ,63 ]. Specifically, the expression of the imprinted gene ZNF331 associates with small head circumference, low birth weight, and small for gestational age. SLC22A18 instead is associated with larger head circumference. &&
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These two imprinted genes have been shown belonging to two clusters, each composed by eight genes, affecting fetal growth in opposite directions. Cluster 1 genes (CD44, CDKAL1, DHCR24, EPS15, ILK, MEST, PEG10, ZNF331) support and cluster 2 genes (HOXA11, HOXD10, IGF2, MEG3, PEG3, PLAGL1, SLC22A18, TP73) limit growth. These data are in agreement with previous results from the investigations on imprinted gene expression and IUGR [64], and also suggest a common underlining fetal programming mechanism. Similarly, the expression of imprinted genes associates with the infant neurobehavior as measured by the Neonatal Intensive Care Unit Network Neurobehavioral Scales (NNNS) test [63 ]. Significant associations were identified between classes of imprinted gene expression and the NNNS quality of movement and handling scores with an independent effect of imprinted gene expression on these neurobehavioral scores. Interestingly, genes associated with poorer quality of movement almost entirely match cluster 1 genes (promoting embryonic growth), whereas genes linked to lower arousal and excitability overlap with the genes in cluster 2 (limiting embryonic growth). Noticeably, data on imprinted gene expression, fetoplacental growth, and infant neurodevelopment have also been confirmed across different sample populations in so identifying expression alterations common to the same genes (i.e. CDKAL1, DHCR24, ILK, MEG3, MEST, PEG10, PLAGL1, ZNF331). Finally, many studies have proven that imprinting status and imprinted gene expression dysregulations lead to transient neonatal diabetes mellitus (type 1) [65 ], metabolic syndrome [66 ,67,68 ], and obesity [69–71], according to the key role that imprinted genes play on the development of metabolic organs. &&
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GENOMIC IMPRINTING AND THE PLACENTA The determination of how alterations of genomic imprinting (both the imprinting status and imprinted gene expression) may affect embryonic growth requires the availability of abundant fetal tissue to conduct molecular studies. Such tissue becomes available at birth with the delivery of the placenta. The placenta is a unique organ that supports and drives embryonic development by providing the environment for the growth of the fetus, coordinating the different phases of embryogenesis, and serving as an interface for maternal–fetal interactions [7 ]. The placenta is a very dynamic organ,
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where a continuum of phenotypic and morphological changes takes place over the course of gestation [72]. Such plasticity is achieved due to a unique epigenetic profile with the lowest level of genomic DNA methylation of all organs across different species [73,74]. Under the assumption that DNA methylation leads to gene silencing, this hypomethylated profile has been attributed to the need for the placenta to sustain implantation with the promotion of rapid and highly coordinated fetoplacental growth and maturation [75]. The placenta shares the genetic and epigenetic profile of the developing embryo as it originates from the blastocyst that will later develop into the embryonic cell mass and the extraembryonic cell layer that will give rise to the placenta [54]. This status affords the unique opportunity of studying the contribution of dysregulations of the imprinting profile on fetal growth and development by using placental tissue. The role of the placenta extends to the determination of the brain growth by synchronizing the expression of several imprinted genes [28]. The placenta also supplies serotonin to the developing brain to support neuronal differentiation up to the 14th week of gestation [76–78]. The placenta is thus the effector of the intrauterine environment representing the target organ for studying the alterations of the imprinting status and imprinted gene expression, as driven by environmental exposures, leading to developmental outcomes.
GENOMIC IMPRINTING AS ENVIRONMENTAL SENSOR AND MARKER OF FETAL GROWTH The recent years of study on genomic imprinting marked the dawn of a new approach toward this unique and fascinating multilayer epigenetic phenomenon. The current opinion on genomic imprinting is that it can be fully characterized into a biomarker for the early detection of developmental disorders in children following the perinatal exposure to toxic environmental stimuli that can alter the imprinting epigenetic inheritance and its closely guarded status. The idea sprang from a molecular epidemiology study, back in 2009, which showed that imprinted genes respond to common environmental stimuli like nutrition and maternal psychosocial stress in pregnancy (MPSP). Insufficient maternal caloric intake due to a famine episode during World War II in the Netherlands (Dutch Cohort Study) has indeed been correlated with lasting DNA methylation changes at several imprinted loci in the progeny like INS, IGF2, GNASAS, and MEG3 [71]. Such 240
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changes were traceable up to 60 years after the triggering event. Epidemiologic investigations on exposed patients concomitantly revealed high rates of behavioral disorders, as mainly schizophrenia and obesity [60,79], as confirmed by other investigations in populations with similar exposures [80]. In agreement with both experimental animal and human studies [26,70,81,82], obesity has been attributed to the programming of the fetus to survive in a food-deprived environment, as conveyed by the mother during the famine, which later turned out to instead provide plenty of calories. On the contrary, the schizophrenia rates observed have been linked to the high MPSP rates experienced during the famine period that translated into a progeny that tends to show psychotic conditions making these individuals more aggressive and suspicious toward others and therefore more fit to adapt to an inhospitable social environment [48]. More recently, the Newborn Epigenetic STudy (NEST), conducted at Duke University, generated a wealth of data on the effects of perinatal environmental exposure and nutrition on child health mediated by imprinting dysregulations [83 ]. Lately, new findings were published that also supported the transgenerational role of genomic imprinting. Paternal obesity has been in fact associated with IGF2 hypomethylation in newborns [84 –86 ]. These data strikingly support those reported by the Dutch Cohort Study in which hypermethylation within this same gene was observed triggered by starvation. Both the Dutch Cohort Study and NEST used blood tissue to conduct their investigations. It is our opinion that blood is less informative because of the high degree of differentiation of its cells and the limited involvement in the developmental process when compared to the placenta. This scenario therefore supports the use of a tissue like the placenta for these types of investigation which is likely to provide more clear and comprehensive information. The Dutch Cohort Study and NEST are the first epidemiologic investigations that linked imprinting alterations to environmental exposures and health outcomes in children. These results are supported by other investigations on both experimental animals and humans that pointed out how genomic imprinting responds to environmental exposure to chemicals by undergoing to alterations during the early stages of the embryo development [87 ] but also earlier on gametes (transgenerational effect) [88 ,89 ]. At the same time, other studies pointed out the great deal of information that can be extracted by analyzing genomic imprinting in placenta to predict the infant neurobehavior at birth, pregnancy outcomes and measures of fetal development [62 ,63 ]. &
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It is now the time to link these information into a birth cohort study that can examine different toxic environmental stimuli, imprinting status and imprinted gene expression and child health outcomes by using placental tissue.
CONCLUSION Plenty of evidences are becoming available that point to genomic imprinting as the determinant of the epigenetic inheritance driving the fetal growth. Genomic imprinting is a multilayer epigenetic phenomenon that responds to environmental exposures of the most diverse origin and can predict developmental alterations in children. Genomic imprinting, once sufficiently characterized, can be developed into a powerful biomarker for the early diagnosis of many developmental disorders in children and can support the implementation of effective plans of intervention for addressing the symptoms brought about by such developmental disorders. Acknowledgements The Author thanks Drs Jia Chen, Carmen Marsit, and Yula Ma for their support in the conduction of the experimental activity that has been cited in this review. Conflicts of interest Supported in part by the Venture Capital Research Funding Program of the Mount Sinai Children’s Environmental Health Center.
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68. Travers ME, Mackay DJ, Dekker Nitert M, et al. Insights into the molecular mechanism for type 2 diabetes susceptibility at the KCNQ1 locus from temporal changes in imprinting status in human islets. Diabetes 2013; 62:987–992. Very interesting research article that analyzes imprinting status and imprinted gene expression in diabetes while also exploring the molecular bases of imprinting dysregulation. 69. Heijmans BT, Kremer D, Tobi EW, et al. Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus. Hum Mol Genet 2007; 16:547–554. 70. Plagge A, Kelsey G, Germain-Lee EL. Physiological functions of the imprinted Gnas locus and its protein variants Galpha(s) and XLalpha(s) in human and mouse. J Endocrinol 2008; 196:193–214. 71. Tobi EW, Lumey LH, Talens RP, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 2009; 18:4046–4053. 72. Hu D, Cross JC. Development and function of trophoblast giant cells in the rodent placenta. Int J Dev Biol 2010; 54:341–354. 73. Ehrlich M, Gama-Sosa MA, Huang LH, et al. Amount and distribution of 5methylcytosine in human DNA from different types of tissues of cells. Nucleic Acids Res 1982; 10:2709–2721. 74. Gama-Sosa MA, Midgett RM, Slagel VA, et al. Tissue-specific differences in DNA methylation in various mammals. Biochim Biophys Acta 1983; 740:212–219. 75. Perry JK, Lins RJ, Lobie PE, et al. Regulation of invasive growth: similar epigenetic mechanisms underpin tumour progression and implantation in human pregnancy. Clin Sci (Lond) 2010; 118:451–457. 76. Davies W, Isles AR, Wilkinson LS. Imprinted gene expression in the brain. Neurosci Biobehav Rev 2005; 29:421–430. 77. Li L, Keverne EB, Aparicio SA, et al. Regulation of maternal behavior and offspring growth by paternally expressed Peg3. Science 1999; 284:330– 333. 78. Wilkinson LS, Davies W, Isles AR. Genomic imprinting effects on brain development and function. Nat Rev Neurosci 2007; 8:832–843. 79. Roseboom T, de Rooij S, Painter R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev 2006; 82:485–491. 80. Song S, Wang W, Hu P. Famine, death, and madness: schizophrenia in early adulthood after prenatal exposure to the Chinese Great Leap Forward Famine. Soc Sci Med 2009; 68:1315–1321. 81. Yu L, Chen M, Zhao D, et al. The H19 gene imprinting in normal pregnancy and preeclampsia. Placenta 2009; 30:443–447. 82. Yu S, Gavrilova O, Chen H, et al. Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism. J Clin Invest 2000; 105:615–623. 83. Perkins E, Murphy SK, Murtha AP, et al. Insulin-like growth factor 2/H19 & methylation at birth and risk of overweight and obesity in children. J Pediatr 2012; 161:31–39. This is the first research article reporting on the role of some key imprinted genes in the development of obesity on children from NEST. 84. Soubry A, Schildkraut JM, Murtha A, et al. Paternal obesity is associated with & IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC medicine 2013; 11:29. This research article suggests a preconceptional impact of paternal obesity on the reprogramming of imprint during spermatogenesis. 85. Soubry A, Murphy SK, Wang F, et al. Newborns of obese parents have altered & DNA methylation patterns at imprinted genes. Int J Obes (Lond) 2013; Epub ahead of print. This research article shows altered methylation at multiple imprint regulatory regions in children born to obese parents. 86. Vidal AC, Murphy SK, Murtha AP, et al. Associations between antibiotic & exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring. Int J Obes (Lond) 2013; 37:907–913. This research article supports inverse association between in-utero exposure to antibiotics and lower infant birth weight. 87. Zhu JQ, Si YJ, Cheng LY, et al. Sodium fluoride disrupts DNA methylation of & H19 and Peg3 imprinted genes during the early development of mouse embryo. Arch Toxicol 2013; Epub ahead of print. This research article reports that the exposure to the toxic chemical sodium fluoride (NaF) may interact directly with the embryo to disrupt the maintenance of normal gene imprinting during pregnancy. 88. Trapphoff T, Heiligentag M, El Hajj N, et al. Chronic exposure to a low & concentration of bisphenol A during follicle culture affects the epigenetic status of germinal vesicles and metaphase II oocytes. Fertil Steril 2013; 100:1758–1767 e1. This research article provides evidence that the exposure to the endocrine disruptor bisphenol A produces disturbances in oocyte genomic imprinting that might affect health of the offspring. 89. Doshi T, D’Souza C, Vanage G. Aberrant DNA methylation at Igf2-H19 & imprinting control region in spermatozoa upon neonatal exposure to bisphenol A and its association with post implantation loss. Molec Biol Rep 2013; 40:4747–4757. This research article indicates that aberrant methylation at the Igf2-H19 imprinting control region in spermatozoa is inherited by embryo causing perturbation in the expression of Igf2 and H19, ultimately leading to post implantation loss. &
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Genomic imprinting: sensing the environment and driving the fetal growth Luca Lambertini a,b
Purpose of review Genomic imprinting is an epigenetically-driven phenomenon that responds to environmental stimuli to determine the fetal growth trajectory. This review aims at describing the transgenerational meaning of genomic imprinting while supporting the study of genomic imprinting in placenta for the determination of an important biomarker of chronic and developmental disorders in children as driven by the environment. Recent findings Recent work has shown that genomic imprinting reaches beyond the basic significance of an epigenetic mark regulating gene expression. Genomic imprinting has been theorized as the main determinant of epigenetic inheritance. Concomitantly, new studies in the field of molecular epidemiology became available that tie the fetal growth trajectory to genomic imprinting in response to environmental stimuli, making of genomic imprinting the driving force of the fetal growth. When carried out in placenta, the effector of the intrauterine environment as conveyed by the maternal exposure to the general life environment, the study of genomic imprinting may reveal critical information on alterations of the fetal growth trajectory. Summary The study of genomic imprinting profiles in placentas from birth cohorts of individuals exposed to different environmental stimuli can provide a new, much needed, tool for the elaboration of effective public health intervention plans for child health. Keywords environment, fetal growth trajectory, genomic imprinting, placenta
INTRODUCTION Genomic imprinting refers to the monoallelic expression of genes accordingly to the parent of origin. Currently, about 90 imprinted genes have been identified and validated in the human genome, while it is expected that some additional 100 genes are imprinted [1 ,2,3,4 ]. Imprinted genes thus represent a rather small subset of the protein-coding genome (1%), which is even smaller if we consider all the known transcripts (less than 0.5%). It has been theorized that genomic imprinting evolved coincidentally with placentation, and its origin is postulated by the ‘parental conflict’ theory, which proposes that genomic imprinting evolved to allow proper distribution of maternal resources to the developing embryo [5,6]. This theory hypothesizes that there is a ‘tug of war’ between the paternally expressed genes that promote fetal growth, and the maternally expressed genes that have the opposite effect in order to preserve maternal energies. Genomic imprinting alterations &
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have been found linked to many developmental disorders in children while concomitantly responding to environmental exposures [7 ]. The review aims at providing a quick overview of the molecular features of genomic imprinting while tying these same features to the determination of the fetal growth trajectory. Evidence will be then provided showing that the study of genomic imprinting alterations in correlation with environmental exposures and child health outcomes can effectively be conducted by investigating the &&
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Department of Preventive Medicine and bDepartment of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, USA Correspondence to Luca Lambertini, PhD, Assistant Professor, Departments of Preventive Medicine and Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, One Gustave L. Levi Place, Box 1057, New York, NY 10029, USA. Tel: +1 212 824 7076; e-mail: [email protected] Curr Opin Pediatr 2014, 26:237–242 DOI:10.1097/MOP.0000000000000072
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KEY POINTS
trajectory of the embryo within a dynamic process intended to generate a progeny that best adapts to the life milieu it will face at birth [13–15,16 ]. Genomic imprinting, however, escapes this embryo re-programming wave supporting the theory that hypothesizes that genomic imprinting is the determinant of the parental epigenetic inheritance [17 ,18,19 ]. This theory is further supported by the discovery that the imprinting status of several imprinted genes/clusters, unlike the vast majority of the epigenetic phenomena that are tissuespecific, is consistently maintained unchanged across tissues/organs [20 ]. Interestingly, the imprinting status of these same imprinted genes may still be detectable in tissues/organs in which the imprinted genes no longer behave as such, but are instead commonly biallelically expressed [21–23]. At the same time, changes in the imprinting status do not directly correlate with changes in gene expression levels [24,25]. Genomic imprinting is thus more likely to represent the inherited organization of the chromatin rather than specifically controlling the expression dosage of imprinted genes by acting on their allele-specific expression [17 ,20 ]. As one of the determinants of the epigenetic inheritance, genomic imprinting has the potential to modify the phenotype if altered during embryogenesis. Accordingly, imprinted genes can be classified into three categories based on their functional roles: (1) genes that control the allocation of maternal resources to the fetus; (2) genes that regulate metabolism in the early postnatal period; and (3) genes that prenatally determine the metabolism of developing metabolic organs such as the pancreas, muscle, fat cells, and the hypothalamus [26,27]. The timely expression of imprinted genes is fundamental for the correct embryo development [28]. Additionally, imprinted gene expression demonstrates low transcriptional noise, as shown in the placenta [24]. This finding is in agreement with the imprinted genes functional importance that, as shown for other such genes [29,30], once altered, can lead to prominent phenotypic changes [31,32] such as lethality [33,34] that may be further enhanced by the constitutional haploinsufficiency of imprinted genes [35]. Given its relative ‘insensitivity’ to the common environmental signals that naturally shape the growth of the embryo and the critical role it plays in the embryo development, genomic imprinting is perfectly positioned to become a powerful biomarker for the detection of disorders brought about by exposures to toxic environmental stimuli that can disrupt both the imprinting status and the imprinted gene expression. &
Genomic imprinting is a transgenerational epigenetic multifactorial phenomenon. Genomic imprinting is sensitive to toxic environmental stimuli. Genomic imprinting can predict several developmental disorders in children. Genomic imprinting is best studied in placenta.
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placenta, the effector of the intrauterine environment. The last part of this review will discuss some of the currently accessible literature that supports the use of imprinting profiling as marker of exposure to ‘toxic’ environmental stimuli leading to alteration of the fetal growth trajectory.
GENOMIC IMPRINTING FEATURES Genomic imprinting is probably the best example of how multiple epigenetic layers act together on determining the phenotype. It has in fact been shown that DNA methylation, histone coding and chromatin-modeling elements like long nonprotein-coding RNAs (lncRNAs), coordinately work in regulating the monoallelic expression of imprinted genes [8,9]. Imprinted genes are often found in clusters regulated by imprinting control regions (ICRs), but single imprinted genes under the control of ICR-like elements (ILEs) are not uncommon. ICRs and ILEs are DNA sequences that determine the imprinting status by carrying the DNA methylation and histone code on the allele that they contribute to silence by also binding transcription regulatory complexes assisted by lncRNAs, which are abundant between imprinted genes [10–12]. ICRs can control the allele-specific expression of imprinted gene clusters ranging from 2 to 9 genes. ICRs may be located several kilobase pairs away from a specific imprinted gene cluster, in noncoding genomic areas or in the promoter or gene body of other imprinted/not imprinted genes. ILEs, on the contrary, are invariably located within the promoter region of imprinted genes that are not clustered [12]. Genomic imprinting shows peculiar features when compared with the vast majority of the other epigenetic phenomena. At fertilization, the epigenetic set-up of the embryo is completely reset to capture the common environmental signals, as conveyed by the mother through the intrauterine environment, that naturally shape the growth 238
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Genomic imprinting, environment and fetal growth Lambertini
GENOMIC IMPRINTING AND DISEASE A vast scientific literature exists that linked alterations of the imprinting status and imprinted gene expression with developmental outcomes as mainly of neural and metabolic origin [36 ]. Alterations of the imprinting status and imprinted gene expression have been linked to severe neurodevelopmental disorders spanning from Beckwith-Wiedemann [37,38], Silver-Russel [39,40], Prader-Willi [41,42], and Angelman [43,44] syndromes all the way to autism spectrum disorders (ASD) [45–47]. These findings form the basis of the ‘imbalanced brain theory’ that may explain, at least partially, the ASD and schizophrenia sexual dichotomies, in which the imbalance of paternally expressed genes in the limbic system to maternally expressed genes in the cerebral cortex, in either direction, leads to the conditions that are characteristics of these two disorders [45,48–50]. Additionally, the fact that imprinting marks are inherited strongly suggests that any imprinting alteration early in development is likely to be detectable in most tissues and to have wide-ranging effects [51]. Other studies showed that imprinted gene expression is altered in placentas from pregnancies with intrauterine growth restriction (IUGR) [24,25]. IUGR is a fairly common pregnancy outcome that has been linked to alterations of the intrauterine environment leading to shallow implantation of the placenta in the uterine wall, hypoxia, vascular lesions, and uteroplacental insufficiency [52–54]. Babies from IUGR pregnancies carry higher risks for the development of coronary heart disease, hypertension, hyperlipidemia, and diabetes mellitus in adulthood (Barker hypothesis [55,56]), but also obesity [57,58] and neurodevelopmental disorders [59,60]. Supporting their functional importance, expression levels of the tested imprinted genes were found very tightly regulated with a limited transcriptional noise. The imprinted gene expression profiling in IUGR identified down-regulated (CCDC86, ILK, NNAT, PEG10, PHLDA2) as well as up-regulated (CDKAL1, DHCR24, PLAGL1, ZNF331) genes. IUGR has also been shown to induce changes in the imprinting status of several imprinted genes (DLK1, H19, PLAGL1, SNRPN) [24,61] as measured by assessing their monoallelic expression. Concomitantly, imprinted gene expression correlates with infant neurobehavior at birth, pregnancy outcomes as fetal growth restriction, and with measures of fetal development like head circumference and birth weight [62 ,63 ]. Specifically, the expression of the imprinted gene ZNF331 associates with small head circumference, low birth weight, and small for gestational age. SLC22A18 instead is associated with larger head circumference. &&
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These two imprinted genes have been shown belonging to two clusters, each composed by eight genes, affecting fetal growth in opposite directions. Cluster 1 genes (CD44, CDKAL1, DHCR24, EPS15, ILK, MEST, PEG10, ZNF331) support and cluster 2 genes (HOXA11, HOXD10, IGF2, MEG3, PEG3, PLAGL1, SLC22A18, TP73) limit growth. These data are in agreement with previous results from the investigations on imprinted gene expression and IUGR [64], and also suggest a common underlining fetal programming mechanism. Similarly, the expression of imprinted genes associates with the infant neurobehavior as measured by the Neonatal Intensive Care Unit Network Neurobehavioral Scales (NNNS) test [63 ]. Significant associations were identified between classes of imprinted gene expression and the NNNS quality of movement and handling scores with an independent effect of imprinted gene expression on these neurobehavioral scores. Interestingly, genes associated with poorer quality of movement almost entirely match cluster 1 genes (promoting embryonic growth), whereas genes linked to lower arousal and excitability overlap with the genes in cluster 2 (limiting embryonic growth). Noticeably, data on imprinted gene expression, fetoplacental growth, and infant neurodevelopment have also been confirmed across different sample populations in so identifying expression alterations common to the same genes (i.e. CDKAL1, DHCR24, ILK, MEG3, MEST, PEG10, PLAGL1, ZNF331). Finally, many studies have proven that imprinting status and imprinted gene expression dysregulations lead to transient neonatal diabetes mellitus (type 1) [65 ], metabolic syndrome [66 ,67,68 ], and obesity [69–71], according to the key role that imprinted genes play on the development of metabolic organs. &&
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GENOMIC IMPRINTING AND THE PLACENTA The determination of how alterations of genomic imprinting (both the imprinting status and imprinted gene expression) may affect embryonic growth requires the availability of abundant fetal tissue to conduct molecular studies. Such tissue becomes available at birth with the delivery of the placenta. The placenta is a unique organ that supports and drives embryonic development by providing the environment for the growth of the fetus, coordinating the different phases of embryogenesis, and serving as an interface for maternal–fetal interactions [7 ]. The placenta is a very dynamic organ,
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where a continuum of phenotypic and morphological changes takes place over the course of gestation [72]. Such plasticity is achieved due to a unique epigenetic profile with the lowest level of genomic DNA methylation of all organs across different species [73,74]. Under the assumption that DNA methylation leads to gene silencing, this hypomethylated profile has been attributed to the need for the placenta to sustain implantation with the promotion of rapid and highly coordinated fetoplacental growth and maturation [75]. The placenta shares the genetic and epigenetic profile of the developing embryo as it originates from the blastocyst that will later develop into the embryonic cell mass and the extraembryonic cell layer that will give rise to the placenta [54]. This status affords the unique opportunity of studying the contribution of dysregulations of the imprinting profile on fetal growth and development by using placental tissue. The role of the placenta extends to the determination of the brain growth by synchronizing the expression of several imprinted genes [28]. The placenta also supplies serotonin to the developing brain to support neuronal differentiation up to the 14th week of gestation [76–78]. The placenta is thus the effector of the intrauterine environment representing the target organ for studying the alterations of the imprinting status and imprinted gene expression, as driven by environmental exposures, leading to developmental outcomes.
GENOMIC IMPRINTING AS ENVIRONMENTAL SENSOR AND MARKER OF FETAL GROWTH The recent years of study on genomic imprinting marked the dawn of a new approach toward this unique and fascinating multilayer epigenetic phenomenon. The current opinion on genomic imprinting is that it can be fully characterized into a biomarker for the early detection of developmental disorders in children following the perinatal exposure to toxic environmental stimuli that can alter the imprinting epigenetic inheritance and its closely guarded status. The idea sprang from a molecular epidemiology study, back in 2009, which showed that imprinted genes respond to common environmental stimuli like nutrition and maternal psychosocial stress in pregnancy (MPSP). Insufficient maternal caloric intake due to a famine episode during World War II in the Netherlands (Dutch Cohort Study) has indeed been correlated with lasting DNA methylation changes at several imprinted loci in the progeny like INS, IGF2, GNASAS, and MEG3 [71]. Such 240
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changes were traceable up to 60 years after the triggering event. Epidemiologic investigations on exposed patients concomitantly revealed high rates of behavioral disorders, as mainly schizophrenia and obesity [60,79], as confirmed by other investigations in populations with similar exposures [80]. In agreement with both experimental animal and human studies [26,70,81,82], obesity has been attributed to the programming of the fetus to survive in a food-deprived environment, as conveyed by the mother during the famine, which later turned out to instead provide plenty of calories. On the contrary, the schizophrenia rates observed have been linked to the high MPSP rates experienced during the famine period that translated into a progeny that tends to show psychotic conditions making these individuals more aggressive and suspicious toward others and therefore more fit to adapt to an inhospitable social environment [48]. More recently, the Newborn Epigenetic STudy (NEST), conducted at Duke University, generated a wealth of data on the effects of perinatal environmental exposure and nutrition on child health mediated by imprinting dysregulations [83 ]. Lately, new findings were published that also supported the transgenerational role of genomic imprinting. Paternal obesity has been in fact associated with IGF2 hypomethylation in newborns [84 –86 ]. These data strikingly support those reported by the Dutch Cohort Study in which hypermethylation within this same gene was observed triggered by starvation. Both the Dutch Cohort Study and NEST used blood tissue to conduct their investigations. It is our opinion that blood is less informative because of the high degree of differentiation of its cells and the limited involvement in the developmental process when compared to the placenta. This scenario therefore supports the use of a tissue like the placenta for these types of investigation which is likely to provide more clear and comprehensive information. The Dutch Cohort Study and NEST are the first epidemiologic investigations that linked imprinting alterations to environmental exposures and health outcomes in children. These results are supported by other investigations on both experimental animals and humans that pointed out how genomic imprinting responds to environmental exposure to chemicals by undergoing to alterations during the early stages of the embryo development [87 ] but also earlier on gametes (transgenerational effect) [88 ,89 ]. At the same time, other studies pointed out the great deal of information that can be extracted by analyzing genomic imprinting in placenta to predict the infant neurobehavior at birth, pregnancy outcomes and measures of fetal development [62 ,63 ]. &
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Genomic imprinting, environment and fetal growth Lambertini
It is now the time to link these information into a birth cohort study that can examine different toxic environmental stimuli, imprinting status and imprinted gene expression and child health outcomes by using placental tissue.
CONCLUSION Plenty of evidences are becoming available that point to genomic imprinting as the determinant of the epigenetic inheritance driving the fetal growth. Genomic imprinting is a multilayer epigenetic phenomenon that responds to environmental exposures of the most diverse origin and can predict developmental alterations in children. Genomic imprinting, once sufficiently characterized, can be developed into a powerful biomarker for the early diagnosis of many developmental disorders in children and can support the implementation of effective plans of intervention for addressing the symptoms brought about by such developmental disorders. Acknowledgements The Author thanks Drs Jia Chen, Carmen Marsit, and Yula Ma for their support in the conduction of the experimental activity that has been cited in this review. Conflicts of interest Supported in part by the Venture Capital Research Funding Program of the Mount Sinai Children’s Environmental Health Center.
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Genomic imprinting effects on brain development and function. Nat Rev Neurosci 2007; 8:832–843. 79. Roseboom T, de Rooij S, Painter R. The Dutch famine and its long-term consequences for adult health. Early Hum Dev 2006; 82:485–491. 80. Song S, Wang W, Hu P. Famine, death, and madness: schizophrenia in early adulthood after prenatal exposure to the Chinese Great Leap Forward Famine. Soc Sci Med 2009; 68:1315–1321. 81. Yu L, Chen M, Zhao D, et al. The H19 gene imprinting in normal pregnancy and preeclampsia. Placenta 2009; 30:443–447. 82. Yu S, Gavrilova O, Chen H, et al. Paternal versus maternal transmission of a stimulatory G-protein alpha subunit knockout produces opposite effects on energy metabolism. J Clin Invest 2000; 105:615–623. 83. Perkins E, Murphy SK, Murtha AP, et al. Insulin-like growth factor 2/H19 & methylation at birth and risk of overweight and obesity in children. J Pediatr 2012; 161:31–39. This is the first research article reporting on the role of some key imprinted genes in the development of obesity on children from NEST. 84. Soubry A, Schildkraut JM, Murtha A, et al. Paternal obesity is associated with & IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC medicine 2013; 11:29. This research article suggests a preconceptional impact of paternal obesity on the reprogramming of imprint during spermatogenesis. 85. Soubry A, Murphy SK, Wang F, et al. Newborns of obese parents have altered & DNA methylation patterns at imprinted genes. Int J Obes (Lond) 2013; Epub ahead of print. This research article shows altered methylation at multiple imprint regulatory regions in children born to obese parents. 86. Vidal AC, Murphy SK, Murtha AP, et al. Associations between antibiotic & exposure during pregnancy, birth weight and aberrant methylation at imprinted genes among offspring. Int J Obes (Lond) 2013; 37:907–913. This research article supports inverse association between in-utero exposure to antibiotics and lower infant birth weight. 87. Zhu JQ, Si YJ, Cheng LY, et al. Sodium fluoride disrupts DNA methylation of & H19 and Peg3 imprinted genes during the early development of mouse embryo. Arch Toxicol 2013; Epub ahead of print. This research article reports that the exposure to the toxic chemical sodium fluoride (NaF) may interact directly with the embryo to disrupt the maintenance of normal gene imprinting during pregnancy. 88. Trapphoff T, Heiligentag M, El Hajj N, et al. Chronic exposure to a low & concentration of bisphenol A during follicle culture affects the epigenetic status of germinal vesicles and metaphase II oocytes. Fertil Steril 2013; 100:1758–1767 e1. This research article provides evidence that the exposure to the endocrine disruptor bisphenol A produces disturbances in oocyte genomic imprinting that might affect health of the offspring. 89. Doshi T, D’Souza C, Vanage G. Aberrant DNA methylation at Igf2-H19 & imprinting control region in spermatozoa upon neonatal exposure to bisphenol A and its association with post implantation loss. Molec Biol Rep 2013; 40:4747–4757. This research article indicates that aberrant methylation at the Igf2-H19 imprinting control region in spermatozoa is inherited by embryo causing perturbation in the expression of Igf2 and H19, ultimately leading to post implantation loss. &
Volume 26 Number 2 April 2014
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