Prof WE Farrell, Institute of Science and Technology in Medicine, Keele University School of Medicine, Hartshill Campus, Hartshill, Stoke-on-Trent, Staffordshire, ST4 7QB, UK. Email email@example.com
Each differentiated cell type has its own epigenetic signature, which reflects its genotype, developmental history, and environmental influences, and is ultimately reflected in the phenotype of the cell and organism. Some cells undergo major epigenetic ‘reprogramming’ during fetal development. The proper, or improper, handling of these highly sensitive periods may have significant short-term and long-term effects on the newborn and his/her progeny. This review highlights the impact of environmental and nutritional factors on the epigenome and the potential effect of epigenetic dysregulation on maternal and fetal pregnancy outcomes, as well as possible long-term implications.
Embryogenesis comprises a series of well-orchestrated events that begins with fertilisation to form a single-cell zygote and ends with a multicellular organism that comprises more than 200 different cell types. The majority of cells within an embryo differentiate into histologically distinct and functionally diverse cell types. Once fully differentiated, the cellular state is stable and heritable.1
The genetic basis of cell differentiation is differential gene expression from the same nuclear repertoire, where different cell types make different sets of proteins, despite the fact that their genomes are identical. The human genome comprises approximately 30 000 genes. Although only a small discrete set of these genes are transcribed within a particular differentiated cell type, a further layer of complexity may be imposed through posttranscriptional and/or posttranslational processing.2,3 Gene expression patterns in the process of differentiation and within the specialised cells themselves are controlled through two principle mechanisms, the first, and perhaps the best understood, is imposed through the DNA sequence itself, while the second is not directly related to the sequence itself and hence termed epigenetic.4,5 Genetic control of gene transcription is dependent on the availability of specific transcription factors that modulate gene expression and these, in turn, recognise control elements (consensus sequences) within the DNA sequence, and thereby regulate gene expression.4 The main focus of this review is to discuss the epigenetic mechanisms involved in the regulation of fetal gene expression.
The stable transmission of cellular information during cell division based on gene expression levels other than that derived from the DNA sequence itself is defined as epigenetic inheritance. For most cell types in the body, these epigenetic marks become fixed once the cell differentiates or exits the cell cycle. However, in discrete developmental stages, and in some disease situations, some cells undergo major epigenetic ‘reprogramming’, involving the removal or modulation of their epigenetic marks.4–6 Four main types of epigenetic inheritance, namely DNA methylation, chromatin remodelling, genomic imprinting, and long-range control by chromatin structure have been described.7,8 Although basically distinct, these mechanisms are frequently interdependent and may be synergistic.
It has been estimated that 3% of the cytosines in human DNA are methylated. Methylation in vertebrate DNA is, in general, restricted to cytosine (C) nucleotides in the sequence CG (annotated CpG). The overall frequency of CpG dinucleotides in the vertebrate genome is low (about 20% of the predicted frequency). However, there are small stretches of DNA that are characterised by having the predicted frequency of CpG dinucleotides, extending for hundreds of bases. These are termed CpG islands.7,8
The methylation status of cytosine residues, within CpG dinucleotides and in the context of CpG islands, provides an important mechanism for distinguishing genes that are active from those that are not.8,9 Approximately half of all transcribed genes have CpG islands, these include all genes that are widely expressed, and about 40% of genes are expressed in a tissue-specific manner. Although 80% of CpGs located outside of CpG islands are methylated, CpG islands are generally not methylated or have very low levels of CpG methylation. The substantially higher mutability of methylated cytosines is believed to be responsible for the decreased frequency of the CpG dinucleotides throughout the genome.10
Classically, the methylation status of a gene is determined by sodium bisulphite sequencing, and the overall methylation status of the genome is determined by high performance liquid chromatography methodologies. For clinical specimens, several high-throughput methods have been described that are, in general, polymerase chain reaction-based. In these cases, genomic DNA is either subjected to prior digestion with methylation-sensitive enzymes or sodium bisulphite conversion. These techniques and methodologies are beyond the scope of this review, and the readers are directed towards a recent excellent review.11
DNA methyltransferases (DNMTs) are enzymes responsible for DNA methylation. The major de novo methyltransferases DNMT3a and DNMT3b are principally responsible for establishing cytosine methylation at previously unmethylated-CpG sites, whereas the maintenance methyltransferase DNMT1 is responsible for maintaining pre-existing methylation patterns. In this case, heritable patterns of CpG methylation are maintained through the propensity of DNMT1 for hemi-methylated DNA. Since DNA replication is semiconservative, this enzyme recognises the methylation associated with the parental strand and imposes this pattern on the newly formed daughter strand of DNA.2,4,5 In this way, the epigenetic pattern, although not part of the DNA sequence itself, is heritably transmitted during cell division.
DNA methylation of CpG islands is associated with transcriptional silencing of the associated gene.10,12 As part of this process, methylated DNA is recognised by a family of methyl-CpG-binding domain (MBD) proteins. The mammalian MBD proteins (MBD1–MBD4) and the founding member, methyl-CpG-binding protein 2 (MeCP2), specifically recognise methylated-CpG dinucleotides. Although all the MBD proteins can mediate chromatin remodelling and gene silencing, the major activity is attributed to MeCP2. Repression is achieved through MeCP2 recruiting chromatin-remodelling co-repressor complexes to regions of DNA that specifically bind the MeCP2 protein.10,13
Inactivating mutations in either DNMT3B or MECP2 are associated with the syndromes of immune deficiency, centromeric instability, and facial anomalies (ICF Syndrome) and Rett syndrome. Rett syndrome is a childhood developmental disorder affecting females, which leads to a progressive loss of motor function and mental retardation. Thus, in these well-documented examples, a genetic change (mutation) is responsible for changing the epigenome expression profile. Abnormal methylation patterns are documented in various malignant processes, with different genes frequently involved, depending on the type of malignancy. The dominant feature in this process is global hypomethylation with hypermethylation of specific CpG islands. Our current understanding indicates a role for abnormal DNA methylation patterns as factors in the development of a wide spectrum of disorders, ranging from systemic lupus erythematosus to schizophrenia. A detailed discussion of the changes related to inappropriate methylation patterns is beyond the scope of this review.14–31
In eukaryotic cells, the DNA is found in the form of a nucleoprotein complex named chromatin, where DNA is found wrapped around the core histone proteins to form the chromatin fibre.32
The modulation of the structure of the chromatin fibre is critical for the regulation of gene expression since it determines the accessibility and the sequential recruitment of regulatory factors to the underlying DNA. Chemical modification of various amino acids constituting the histone proteins can significantly alter the structure of the chromatin fibre, its degree of compaction, and hence the access of the transcription machinery to the DNA within. Histone protein modifications include methylation, acetylation, phosphorylation, ubiquitination, and ADP-ribosylation.10,33,34
The expression of the underlying genetic code is, therefore, achieved through the combinatorial modifications of key amino acid residues of core histones or a ‘histone code’.35,36 Core histone acetylation, for instance, is generally associated with a relaxed higher order chromatin structure, and this is thought to permit or facilitate access of gene regulatory proteins that include transcription and elongation factors. Histone methylation is frequently associated with gene silencing, whereas phosphorylation is associated with chromosome condensation and is seen in cell cycle progression during mitosis or meiosis.32 Thus, a complex pattern emerges where epigenetic change imposed on the DNA sequence itself and on the associated histones ‘dictates’ the transcriptional ‘competence’ of a particular gene. These patterns are interlinked, frequently interdependent and usually tightly controlled.
Genomic imprinting in mammals describes the situation where there is nonequivalence in expression of alleles at certain gene loci, dependent on the parent of origin.37,38 The expression of either the paternally or maternally inherited allele is consistently repressed, resulting in monoallelic expression of a particular gene. The same pattern of monoallelic expression is faithfully transmitted to daughter cells following cell division.3 This phenomenon is not entirely unique to eutherian (placental) mammals39 as it also happens in plants, where most commonly the paternal genes are imprinted.40
Fifty-three human genes are reported to be imprinted to date.41 Thirteen additional genes show conflicting or provisional evidence for imprinting. The imprinted human genes are located in 16 chromosomal regions or clusters. Thirty-five of the imprinted components are protein coding.33,42
The majority of imprinted genes are organised into large chromosomal domains, comprising CG-rich, differentially methylated regions termed ‘Imprinting Control Regions’ (ICRs). ICRs are up to several kilobases in length and are responsible for directing both the silencing of one allele and expression of its homologue. ICRs are regulated by epigenetic modifications, where DNA methylation of one of the two parental alleles is associated with the silenced allele.43
Abnormal imprinting patterns are associated with disorders affecting growth and neurodevelopment. Prader–Willi and Angelman syndromes are two clinically distinct diseases, which are associated with abnormal imprinting on chromosome 15q11-q13. Loss of maternal imprinting is responsible for the Angelman syndrome, which is characterised by mental retardation, ataxia, and social disposition. In Prader–Willi syndrome, loss of paternal imprinting in the same region is characterised by learning difficulties, hypogonadism, short stature, and small hands and feet. Beckwith–Weidemann syndrome, another imprinting disorder characterised by macrosomia, hemihypertrophy, abdominal wall defects, organomegaly, and susceptibility to Wilm’s tumour, is the result of loss of imprinting of insulin-like growth factor-II (IGF-II) on chromosome 11p15.25,44
Long-range control by chromatin structure
Several studies suggest that the genomic context of intact genes, with respect to chromosomal location, influences gene expression. These studies provided evidence that chromosomes are organised into functional domains of gene expression and ‘silent domains’ (chromatin domains). For example, when genes are translocated to new chromosomal regions (either as a result of spontaneous chromosome breakage events or in genetically manipulating model organisms), aberrant gene expression frequently occurs, even though the entire gene and the required control sequences in its immediate neighbouring sequences are preserved.45
Long-range effects can be mediated by several mechanisms including competition for gene enhancer/silencer proteins (e.g. globin gene expression), heterochromatin-induced positional suppression of gene expression (facioscapulohumeral muscular dystrophy), or control of several genes by a common Locus Control Region (also in globin genes).2,4,5
The dynamic state of the epigenetic code
Each differentiated cell type has its own epigenetic signature, which reflects genotype, developmental history, and environmental influences. This is ultimately reflected in the phenotype of the cell and organism. For most cell types in the body, these epigenetic marks become fixed once the cells differentiate or exit the cell cycle. However, in normal developmental or disease situations, some cells undergo major epigenetic ‘reprogramming’. This involves the removal of epigenetic marks in the nucleus, followed by establishment of a different set of marks.4,46 The proper, or improper, handling of these highly sensitive periods may have significant short-term and long-term effects on the individual and his/her progeny. Much of our understanding of the dynamics of the epigenetic code was initially derived from animal models, commonly mice. In general, the information derived with respect to epigenetic programming is common and extends from mouse models to humans. For convenience and clarity, the physiology and later the pathophysiology of epigenetic reprogramming dynamics may be studied in four distinct phases: fertilisation, early embryo development, gametogenesis, and lifelong reprogramming (Figure 1).
The first phase of methylation reprogramming occurs between fertilisation and formation of the blastocyst. Postfertilisation, a rapid paternal-specific asymmetric loss of methylation is observed.47,48 This process takes place in the absence of transcription or DNA replication and is termed active demethylation. This involves the whole paternal genome but spares paternally imprinted genes, heterochromatin around centromeres, and some repetitive elements.46 The mechanism of active demethylation is not clear but may be dependent on factors associated with the sperm nucleus and cytoplasmic maturity of the oocyte.49,50 Thereafter, there is a stepwise decline in methylation until the morula stage.51,52 This decline occurs as a result of the absence of maintenance methylation during DNA replication.53 Thus, the newly replicated strand fails to become methylated, and the level of methyl cytosine per nucleus declines. This replication-dependent loss of DNA methylation is referred to as passive demethylation.
Early embryo development
The initiation of the de novo methylation occurs after the fifth cell cycle and coincides with the time of the first differentiative event. The establishment of the first two cell lineages results in yet another significant asymmetry. The inner cell mass (ICM), which gives rise to all the tissues of the adult, becomes hypermethylated, while the trophectoderm, which forms most of the structure of the placenta, is hypomethylated.52,54 This asymmetry in DNA methylation patterns is maintained and reflected in highly methylated somatic tissues and the distinctively hypomethylated trophoblastic tissues of the placenta.
Among the somatic tissues that are derived from the ICM are the highly methylated primordial germ cells (PGCs), which arise in the extra-embryonic mesoderm of the developing embryo. Their migration through the allantois to the developing germinal ridges, where they will eventually differentiate into mature gametes, completes this cycle of epigenetic reprogramming.55–57
During the early phase of differentiation, PGCs appear to be methylated. In the transitional phase between establishment in the primitive streak and migration to the genital ridge, the genome-wide methylation is no longer observed. This rapid decline suggests that the loss of DNA methylation results from an active targeted process of DNA demethylation.58
This period of profound methylation erasure is associated with the essential resetting of parent-of-origin-specific methylation marks, which must later match the sex of the developing embryo. Around day 12–13 postfertilisation, most sequences have become maximally demethylated.56 Thereafter, gametogenesis is arrested, the female gametes in meiotic prophase and the male in mitosis.
In female embryos, the gonad forms as an ovary with germ cells forming primordial follicles. As long as the primordial follicle and the oocyte contained within it are not activated to enter the growing population, the methylation level of the oocyte genome remains low and unchanged.13 It is during the growth phase of the oocyte that the maternal imprints are laid down on the genome. The imprints are not all established at the same time; instead, each imprinted gene will become methylated at a predetermined time point. During the period of oocyte growth, the general level of DNA methylation increases as both the appropriate maternal pattern of imprinting is laid down and nonimprinted sequences also become methylated.
In male embryos, as with the oocyte, new imprints are laid down as sperm develop, with the increase in DNA methylation levels not just attributable to the establishment of paternal imprints but also the methylation of other nonimprinted sequences.59
Lifelong epigenetic reprogramming: Ageing, diet, and environmental toxins
DNA methylation patterns are not fixed in the postnatal life. The patterns change with ageing in a complex fashion. Early studies, measuring the total methyl cytosine content of the genome, show definite patterns of global hypomethylation in ageing humans, demonstrated in brain, liver, small intestine mucosa, heart, spleen, and T lymphocytes. Age-related gene methylation changes occur in a tissue-specific fashion and involve gene promoters, as well as noncoding DNA sequences.60–62
Global DNA hypomethylation has been shown to occur with age-related diseases, such as autoimmune pathologies and the development of cancer in humans and mice. Age-dependent methylation changes in CpG islands are not limited to hypomethylation. Hypermethylation of tumour suppressor gene (TSG) CpG islands with age also increases the risk of cancer. In these cases, studies have shown age-related hypermethylation of the estrogen receptor gene in colon mucosa, and other cancer development genes show a linear increase in promoter methylation with age.60–65
Various mechanisms have been proposed to explain the change of DNA methylation status with age. Some studies associate global hypomethylation with an endogenous decline of effective DNMTs expression with age. Other studies pointed to exogenous factors as transient exposures to DNA methylation inhibitors, drugs, or dietary deficiencies. The explanation of focal hypermethylation (that targets specific CpG islands) has been more elusive. In these cases, the spreading of methylation from heterochromatin to euchromatin regions has been proposed.66,67
Diet has been shown to dynamically affect DNA methylation status. The methyl groups of 5′ methyl cytosine are either synthesised de novo during metabolism or are supplied from the diet. Global methylation patterns are susceptible to an excess or deficiency of a variety of dietary elements. They include methyl-deficient diets that cause most global hypomethylations. Interestingly, the methyl deficiency that causes global DNA hypomethylation can simultaneously occur with gene-specific hypomethylation or hypermethylation. In these cases, animal models have been instructive. Mice fed on a folate-deficient diet have been shown to develop overall global DNA hypomethylation and concomitant gene-specific hypermethylation. Similarly, increased CpG island methylation was observed with excess dietary folate supplementation (Figure 2).59,61,62,67
Exposure to environmental chemicals and toxins may lead to chemical modification of cytosines. Cisplastin and budesonide are known to induce methylation, whereas 5-azacytidine and 2′-deoxy-5-azacytidine (DNMT1 inhibitors) are known to cause global DNA hypomethylation. Other toxins which affect DNA methylation include phytochemicals and polyphenolics. The effects of alcohol consumption on DNA methylation have not been reported, although its effect on folate metabolism has been clearly demonstrated.61
Potential implications of epigenetic modulation in obstetrics
The epigenome is particularly susceptible to dysregulation during gestation, neonatal development, puberty, and old age. Indeed, it is perhaps at its most vulnerable to environmental factors during embryogenesis since the DNA synthetic rate is high, and the elaborate DNA methylation patterning and chromatin modifications required for normal tissue development are established during these early development stages.68 The importance of this is emphasised still further by studies demonstrating that the influence of environmental factors on epigenetic gene regulation may also persist transgenerationally, despite the lack of continued exposure, in the second, third, and fourth generations.68–72
The observation that individual subjects who were small or disproportionately large at birth had higher occurrence of adult obesity,73 coronary artery disease,74 hypertension,75 and type II diabetes at middle age and has led to the so-called ‘fetal origins hypothesis of adult disease’, also referred to as the ‘Barker hypothesis’.76,77 The hypothesis states that ‘alterations in fetal nutrition and endocrine status result in developmental adaptations that permanently change structure, physiology, and metabolism, thereby predisposing individuals to cardiovascular, metabolic, and endocrine disease in adult life’. The phenomenon, based on purely epidemiological studies, implied what biologists refer to ‘developmental plasticity’ to convey the ability to change structure and function in an irreversible fashion during a critical time window in response to an environmental cue.78,79
The concept of developmental plasticity was further elaborated by Gluckman and Hanson78,79 who proposed the ‘predictive adaptive response’ hypothesis. It postulates that the developing fetus assesses the plane of nutrition it receives in utero, predicts the postnatal nutritional plane (low or high) that it will encounter, and adapts to the predicted environment in a way that would give it the best chance of survival. If the diet in adulthood diverges from the predicted plane, disease manifests itself. Maternal diet may also have a lifelong effect on gene expression with the potential to cause susceptibility for chronic diseases in adulthood. Hence, nutritional ‘metabolic imprinting or programming’ secondary to under-/over-nutrition at a critical stage during fetal development may provide a plausible explanation for the predictive adaptive response.62,80–82
Maternal under-nutrition during gestation reduces placental and fetal growth of both domestic animals and humans.83,84 Available evidence suggests that fetal growth is most vulnerable to maternal dietary deficiencies of nutrients (e.g. protein and micronutrients) during the peri-implantation period and the period of rapid placental development.62 In this context, dietary deficiency of amino acids results in marked reduction in genomic global DNA methylation.85 Whatever the underlying cause for intrauterine growth restriction, it is likely to involve the growth hormone (GH)/IGF axis with distinct changes in the growth factors and their interaction with corresponding receptors.86 Interestingly, the IGF-II-H19 gene complex is reciprocally imprinted, where IGF-II is paternally expressed in the fetus and placenta. This gene complex is thought to play a role in matching the placental nutrient supply to fetal nutrient demands. Imprinting, in this case, depends on differential methylation. Both increased and decreased expression of IGF-II alter placental size and efficiency.87 Hence, early malnutrition may alter the methylation pattern, with consequences for placental function and embryo development. Deletion of this gene in mice lead to a decrease in the passive permeability for nutrients of the placenta with compensatory secondary active placental amino acid transport upregulation, thus compensating for the decrease in the passive permeability. Later the compensation fails and fetal growth restriction ensues.88,89
GH is encoded by a multi-gene cluster composed of five genes on chromosome 17. Despite their close juxtaposition and strong structural conservation, the five genes display distinct and mutually exclusive tissue specificities. Four of these genes are expressed in the syncytiotrophoblast cellular layer that lines the fetomaternal interface of the placental villi. Studies suggest that the four placental genes are activated by an epigenetic pathway, distinct from the pituitary one, and involving histone modification.90
Hypothetically, intrauterine epigenetic reprogramming of the GH/IGF axis may influence postnatal growth and insulin resistance, serving as the link between fetal growth and adult-onset disease.86,91
Folate supplementation during pregnancy
Humans ingest approximately 50 mmol of methyl groups per day of which 60% are derived from choline. Dietary folate is an important co-factor in regulating methyl group metabolism and, using homocysteine as a methyl carrier, is used to produce S-adenosyl methionine; the principal methyl donor and precursor for DNA methylation (Figure 2). Moreover, excess or deficiency of endogenous or exogenous choline, methionine, folic acid, vitamin B2, vitamin B6, vitamin B12, and zinc may alter the methyl supply. Such a change is expected to affect DNA methylation.61
Adverse effects of deficiencies in folate supply during pregnancy have been the subject of extensive studies and literature reviews.92–94 In addition to the well-established risk of neural tube defect,95 low concentrations of dietary and circulating folate are associated with increased risks of preterm delivery,93 infant low birthweight, and fetal growth retardation.96 Folate deficiency has also been linked with defective maternal erythropoiesis, defective growth of the uterus and mammary gland, and growth of the placenta,96,97 placental infarctions and premature rupture of membranes.98 The subsequently elevated maternal homocysteine concentrations, a metabolic consequence of folate deficiency, has been associated both with increased recurrent miscarriage,99,100 placental abruption,101,102 and pre-eclampsia.103
The epigenetic impact of folate is established in the biomedical literature. Genomic DNA methylation status was found to correlate directly with folate status and inversely with homocysteine levels. In mouse models, Waterland and Jirtle demonstrated that early nutrition could influence the establishment of epigenetic marks in the early embryo, thereby affecting all tissues, including the germline. They concluded that merely supplementing a mother’s nutritionally adequate diet with extra folic acid, vitamin B12, choline, and betaine can permanently affect the offspring’s DNA methylation at epigenetically susceptible loci. These findings support the conjecture that population-based supplementation with folic acid, intended to reduce the incidence of neural tube defects, may have unintended influences on the establishment of epigenetic gene regulatory mechanisms during human embryonic development.104–106 Folate status also affects the expression of sex-linked and imprinted genes, and this effect is not limited to early life,107,108 implying possible maternal, as well as fetal consequences.
Epigenetic regulation of placental gene expression and function
Epigenetic dysregulation can also affect the epigenetically plastic placenta, impairing its size and function, and predisposing to placental pathologies. Several imprinted genes are critical for placental development and function. Indeed, knockout mouse models that have investigated deletion of imprinted genes demonstrate effects on the growth, thickness, and organisation of the placental tissues. Although not invariant deletion of the paternally expressed genes results in a smaller size placenta, the deletion of the maternally expressed genes results in overgrowth of the placenta.89,109–113 Interestingly, imprinting in the placenta seems to be due to histone modifications and noncoding RNAs that are thought to direct DNA methylation.114
Epigenetic control of placental gene expression may play a role in the pathogenesis of pre-eclampsia. Although women with pre-eclampsia typically develop clinical signs and symptoms from mid-gestation, it is now widely accepted that the pathological process starts very early, secondary to an inadequate trophoblastic invasion. Animal studies involving uniparental disomy for imprinted genes on mouse chromosome 12 showed failure of the complete transformation of the wall of the central maternal artery within the decidua basalis, indicating that genomic imprinting may be required in this process, and implying that a defect in the epigenetic control of a maternally expressed imprinted gene might underlie pre-eclampsia.115–118
Moreover, the serine protease inhibitor (SERPIN) superfamily serves as storage proteins, carrier proteins (steroid-binding globulin), and hormone precursors (angiotensinogen or SERPIN A8). They are homeostatic guardians that regulate several molecular pathways, such as inflammation, coagulation, fibrinolysis, complement activation, and phagocytosis. The epigenetic and orchestrated expression of particular TSGs seems to be essential for the complex process of placentation. Maspin (SERPIN A5), a TSG, is differentially expressed in the placenta, with very low levels of expression in the first trimester (maximal trophoblastic proliferation) and higher levels in the second and third trimester. The variable expression of maspin was shown to correlate with histone tail modifications rather than promoter methylation,119 while the expression of RASSF1A, another TSG, seem to be controlled by promoter methylation120 The hypomethylated promoter of maspin, compared with its maternal counterpart, is used as a marker to quantify free fetal DNA in maternal plasma, serving as a predictor of pre-eclampsia, preterm labour, and fetal trisomy 21.121 The expression of members of SERPIN superfamily is induced by hypoxia. Several studies have demonstrated changes in the methylation status of the genes encoding a number of proteins belonging to the SEPRIN family in placentas of pre-eclamptic and control pregnancies, which may suggest a causal relationship.118
In mammals, both X chromosomes are active in the early female embryo. X chromosome inactivation (XCI) occurs at an early stage in development, being initiated at the late blastocyst stage. In each cell that will give rise to the female fetus, one of the two parental X chromosomes is randomly inactivated (with the exception of trophoblast cells where the paternal X chromosome is preferentially inactivated). After the paternal or maternal X chromosome is inactivated in a cell, the same X chromosome usually remains inactive in all progeny cells. Thus, female mammals are mosaics, comprising mixtures of cell lines in which either the paternal or maternal X chromosome is inactivated.2,3,7 The process of XCI involves initial coating of the chromosome by a noncoding RNA, which is coded for by an ‘X inactivation centre’ on the X chromosome destined for inactivation. This is followed by recruitment of histone-modifying protein complexes, which lead to loss of acetylation, gain of methylation, and ubiquitination of various histone proteins. DNA methylation does not appear to be important for this process.114
Recurrent miscarriage is an important medical problem, affecting 1–2% of couples wishing to have children. However, 37–79% of couples receive no explanation for their pregnancy losses. Bagislar et al. demonstrated the ‘skewed X chromosome inactivation’ explanation for at least some of such idiopathic cases.122 This is based on the fact that females, as discussed above, display mosaicism according to whether the paternal or the maternal X chromosome is inactivated. While the choice of which X chromosome to inactivate is generally a random event, under extraordinary circumstances, exclusive, or almost exclusive, inactivation of one X chromosome leading to skewed XCI may be observed. Accordingly, X chromosomal mutations that are cell lethal or associated with cell-growth disadvantage could be tolerated in females as a result of the XCI process and based on the assumption that they are found on inactive X chromosome. Thus, in those cells in which the mutant X chromosome is active (i.e. not silenced), cell death eventually occurs during development and the XCI pattern becomes skewed. At the phenotypic level, the carrier female lives and exhibits no symptoms. However, in males, as there is only one X chromosome that is always active, the putative cell lethal mutation becomes a male lethal trait, and thus contributes to the aetiology of recurrent miscarriage.122–127
Aberrant epigenetic gene regulation has been proposed as a mechanism for several diseases, including carcinogenesis, imprinting disorders, Alzheimer’s disease, schizophrenia, asthma, and autism. This review highlights the impact of environmental and nutritional factors on the dynamic state of the epigenome and the potential role of epigenetic dysregulation in determining maternal, fetal and long-term outcomes. Obstetricians are undoubtedly responsible for providing care to women and their fetuses during some of the most dynamic windows for epigenetic reprogramming. At these times, and in these cases, improper handling of these highly critical periods can modify the epigenetic code and consequently gene function. The importance of this is emphasised even further by evidence demonstrating that epigenetic modifications may persist transgenerationally despite the lack of continued exposure to environmental influences in future generations.
Dr T.M.N. is a research fellow funded by the Egyptian Cultural Bureau, London.
Contribution to authorship
T.M.N.: Article design and drafting. W.E.F.: Critically revising and substantially contributing to the basic science content of the review and approving its final version. W.D.C.: Critically revising the basic science and clinical content of the article and approving its final version. A.A.F.: Critically revising the basic science and clinical content and approving its final version. K.M.K.I.: Critically revising and substantially contributing to the clinical content of the review and approving its final version.