what epigenetics is and why it is thought to be important
van Otterdijk, S.D., and Michels, K.B. (2016). Transgenerational epigenetic inheritance in mammals: how good is the evidence? FASEB Journal, (30), p. 2457-2465. This is a review article that summarizes a number of research studies related to epigenetic inheritance and the state of the research in that area as of 2016. Please refer to the section on epigenetic inheritance in your textbook on page 217. This assignment is due no later than April 22nd, 2019 in Blackboard. You will not understand all of the terms or ideas covered in this article, and that’s ok. For the questions below, please refer to the appropriate sections of the article as indicated in order to answer each question. Please type your answers on a separate sheet of paper. Do not put your answers in the spaces below. 1. (20 points) Using information provided on pages 2457-2458, discuss:
a. what epigenetics is and why it is thought to be important b. what are the primary mechanisms involved in epigenetic inheritance c. what sorts of cellular changes may occur as a result of epigenetics
2. (20 points) Referring to page 2458, discuss how epigenetics might have evolutionary influences. 3. (20 points) Also on page 2458, there is a discussion of intrauterine exposures and how that might affect the fetus’s phenotype. What are some known exposures that affect the fetus in this way? 4. (20 points) Referring to page 2459, discuss how/why genomic imprinting may be the strongest evidence for transgenerational epigenetic inheritance. 5. (10 points) On pages 2462-2463, summarize the main points of the authors’ discussion and conclusions. Does transgenerational epigenetic inheritance exist? What might be some limitations of studying this in humans? 6. (10 points) Using the RMU Library database system, find a primary literature article that is related to this topic. Provide the full citation for this article as the answer to this question.
THE
JOURNAL • REVIEW • www.fasebj.org
Transgenerational epigenetic inheritance in mammals: how good is the evidence? Sanne D. van Otterdijk* and Karin B. Michels*,†,‡,1
*Institute for Prevention and Cancer Epidemiology, University Medical Center Freiburg, Freiburg, Germany; †Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; and ‡Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
ABSTRACT: Epigenetics plays an important role in orchestrating key biologic processes. Epigenetic marks, including DNAmethylation, histones, chromatin structure, andnoncodingRNAs, aremodified throughout life in response to environmental and behavioral influences. With each new generation, DNA methylation patterns are erased in gametesandresetafter fertilization,probably toprevent theseepigeneticmarks frombeing transferred fromparents to their offspring. However, some recent animal studies suggest an apparent resistance to complete erasure of epigenetic marks during early development, enabling transgenerational epigenetic inheritance. Whether there are similar mechanisms in humans remains unclear, with the exception of epigenetic imprinting. Nevertheless, a distinctly different mechanism—namely, intrauterine exposure to environmental stressors that may affect estab- lishment of the newly composing epigenetic patterns after fertilization—is often confused with transgenerational epigenetic inheritance. In this review, we delineate the definition of and requirement for transgenerational epi- genetic inheritance, differentiate it from the consequences of intrauterine exposure, and discuss the available evidence in both animal models and humans.—Van Otterdijk, S. D., Michels, K. B. Transgenerational epigenetic inheritance in mammals: how good is the evidence? FASEB J. 30, 2457–2465 (2016). www.fasebj.org
KEY WORDS: DNA methylation • intrauterine exposure • reprogramming • imprinting • IAP elements
Epigenetics is the meiotically and mitotically herita- ble potential for gene expression that does not involve variation in the DNA sequence (1, 2). Epigenetic events are important in orchestrating key biologic processes, such as cell differentiation, genomic imprinting, and X- chromosome inactivation (3–5). The primarymechanisms involved in epigenetic regulation include DNA methyl- ation, posttranslational histone modification, chromatin remodeling, and RNA-associated gene silencing by non- codingRNAs. Epigeneticmechanismsmediate diversified gene expression profiles to allow the generation of the variety of cells and tissues required in multicellular organisms. All cells in an organism contain essentially the same information, but different cell types vary in their phenotype, function, and expression profiles (6–9). Whereas an organism’s genetic information does not change during its life span (with the exception of acquired
mutations and DNA damage) epigenetic signatures are plastic (10–12) and can be modified in response to envi- ronmental and behavioral influences, such as nutrition, smoking, and air pollution (13–15). Alterations in the epigenome can result in subtle changes in cell differentia- tion or gene expression profiles or can result in cumulative detrimental effects in a cell and may compromise the normal function of the respective gene. Many diseases are associatedwith epigenetic changes. Epigenetic aberrations aremost extensively studied in cancer, but variation in the epigenome has also been described in cardiovascular dis- eases, autoimmune diseases, metabolic disorders, and neurodegenerative diseases (16–18).
Thus, although epigenetic variability enables relevant plasticity to adapt to environmental and lifestyle condi- tions, epigenetic aberrations may predispose to disease, and transferring the acquired epigenetic marks from parents to their offspring could affect the offspring’s de- velopment, plasticity, and disease susceptibility. The epi- genetic signature is erased in gametes and reset after fertilization, likely to prevent genome-wide epigenetic inheritance. In mammals, genome-wide DNA demethy- lationoccurs in 2 stepsduring early development. The first complete demethylation occurs in the parental gametes when the DNA methylation marks are erased in 2 steps accompanied by the restoration of developmental potency (19). An active and rapid demethylation event mediated
ABBREVIATIONS:DNMT, DNA methyltransferase; DOHaD, developmental origins of health and disease; DPPA, developmental pluripotency associ- ated; DZ, dizygotic; IAP, intracisternal A particle; lnRNA, long noncoding RNA; LTR, long terminal repeat; miRNA, microRNA; MZ, monozy- gotic; ncRNA, noncoding RNA; PGC, primordial germ cell; TET, 10–11 translocation 1 Correspondence: Obstetrics and Gynecology Epidemiology Center, Brig- ham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave., Boston, MA 02115, USA. E-mail: kmichels@bwh.harvard.edu
doi: 10.1096/fj.201500083
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by 10–11 translocation (TET) proteins is followed by a passive loss of DNA methylation marks during sub- sequent cell divisions. It has been thought that active demethylation mainly occurs in the paternal gametes and that the maternal gametes were mainly passively deme- thylated (20–22), because the maternal pronucleus may be protected from TET3-mediated conversion by devel- opmental pluripotency associated (DPPA)-3 (also known as stella) (23). However, in a recent study, Guo et al. (24) suggested that both active demethylation by TET3 and passive demethylation are important in both parental gametes. Other mechanisms, such as the base excision repair systems, may also operate in conjunction with the TETproteins, todriveDNAdemethylation (25). Following this first set of demethylation, reestablishment of DNA methylation marks commences during the establishment of the primordial germ cells (PGCs). The second general demethylation occurs after fertilization in the inner cell mass of the developing embryo (26).De novomethylation is established in the blastocyst associated with cellular differentiation.
Notably, differentiallymethylated regions of imprinted genes and retrotransposable elements are exempted from this second de- and remethylation step. In both mice and humans, imprinted regions undergo rapid DNA deme- thylationduring early germ-linedevelopment (27–29), but they are protected from the second round of demethyla- tion,whichenables themtomaintain theirparent-of-origin methylation state (30–32). In mouse models some other repeats, such as intracisternal A particle (IAP), endoge- nous retroviral sequence-1, and single copy sequences, have also been reported to escape epigenetic reprogram- ming (33–35). Whether this resistance to the second de- and remethylation pathway manifests an evolutionary path to ease transfer of epigenetic marks from parent to offspring remains unclear, but intergenerational inheri- tance may provide some functional advantages. For ex- ample,maintenance ofmethylationmaybe necessary to prevent transcriptional activity of the transposable el- ements and may reduce the risk of germ-line mutations through dysregulation of adjacent genes (27).
The evolutionary potential of the epigenetic code links back to theories of both Lamarck and Darwin. Lamarck proposed that the environment alters pheno- type in a heritable manner, which is consistent with the concept that environmental exposures at critical devel- opmental windows can promote epigenetic inheritance of epimutations in the germ line, which may increase phenotypic variation (36). Darwin argued that natural selection favors the survival or reproductive success of those with the greatest ability to adapt (36). This theory favors intergenerational plasticity and heritable adap- tive phenotypic variation.
Transgenerational epigenetic inheritance requires an incomplete erasure of the epigenetic signature during de- velopmental reprogramming permitting the transfer of epigenetic marks from parents onto their offspring over subsequent generations. Most studies investigating this phenomenon are based on animal models, leaving it un- clear whether transgenerational epigenetic inheritance ex- ists in humans. Moreover, germ-line inherited epigenetic
traits must be differentiated from intrauterine exposures, as both may shape the neonates epigenetic profile and can result in similarities between parents and offspring in their epigenetic code and phenotypes.
In this review, we will define the concept of trans- generational epigenetic inheritance, discuss the available data, and draw distinctions between transgenerational epigenetic inheritance and other phenomena, such as in- trauterine exposures, and their implications for the estab- lishment of the epigenome after fertilization.
INTRAUTERINE EXPOSURES
Any environmental stressor that acts during early devel- opmentmay affect the establishment of the epigenome and in turn the individual’s phenotype in the short and long term. For this reason there has been considerable interest among the Developmental Origins of Health and Disease (DOHaD) community in exploring the epigenetic under- pinningsof exposuresduringpregnancy thataffect later-life susceptibility to chronic disease (37, 38). The fetus is ex- posed in utero to some of the same environmental stressors as the mother. As a result, intrauterine experiences may induce fetal reprogramming via alterations in the epigenetic code before birth, with no inheritance from the parents.
The epigenome is thought to be particularly vulnerable to environmental factors during embryogenesis, which becomes evident from numerous studies that have re- ported serious consequences in later life caused by in- trauterine stressors. In animal studies, altered levels of the offspring’s stress response, glucosemetabolism, blood pressure, cholesterol metabolism, and cardiac energy metabolismwere related tomaternal diet, stress, and even traumatic exposures during pregnancy, and these associ- ations were complemented by differential epigenetic pat- terns and differentially expressed genes (35, 39–43). Maternal behavior may also affect offspring epigenetics. The levels ofmaternal licking, grooming, and arched-back nursing in mouse pups have been reported to influence their level of fearfulness. The impact of maternal care on the development of stress reactivity has been suggested to be mediated by changes in the levels of expression of specific genes inbrain regions that regulate behavioral and endocrine responses to stress (44), and maternal behavior has been suggested to alter DNA methylation and chro- matin structure in these pups (44, 45). However, these observations still have to be confirmed by other research groups.
In humans, parental nutritional and smoking behavior during pregnancy affect the offspring’s risk of cardiovas- cular and metabolic diseases, schizophrenia, and antiso- cial personality disorders (46–49); however, any epigenetic involvement remains less clear. Whereas maternal smok- ing has consistently been linked to demethylation of the AHRR gene, the methylation status of the human NR3C1 gene in newborns is sensitive to prenatal maternal mood, and periconceptional exposure to famine has been asso- ciated with lower DNA methylation of the IGF2 gene in adulthood(50–52), examplesofepigeneticdifferences linking prenatal exposures and adult disease outcomes are still
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missing, primarily because of the lack of availability of biospecimens at birth in longitudinal studies.
TRANSGENERATIONAL EPIGENETIC INHERITANCE
Intergenerational epigenetic inheritance is the transfer of epigenetic marks from the gametes to the embryo for 1 generation. It requires incomplete erasure of the parental epigenetic marks, thus avoiding epigenetic reprogram- ming in the gametes and during early embryo develop- ment. For transgenerational epigenetic inheritance to occur, epigenetic marks and phenotypes must be trans- ferredacross subsequentgenerations. Inagestating female, the phenotypic changes would have to be maintained for at least 4 generations. When the gestating mother (F0) is exposed to an environmental challenge, her embryo (F1) and the already developing germ line (F2) of the embryo, are also directly exposed (Fig. 1). Thus, a third generation’s phenotype may result from the grandmother’s experi- ences via intrauterine exposure and does not represent inheritance. In investigationsof exposures operatingbefore gestation via the maternal germ line or of inheritance via the paternal germ line, the third-generation offspring phe- notype is sufficient to establish transgenerational epige- netic inheritance (53, 54).
Epigenetic marks may be inherited through several pathways. We will discuss these in the sections below.
IMPRINTING
The strongest evidence for transgenerational epige- netic inheritance in mammals is genomic imprinting. Imprinted genes are expressed by only one of the 2 pa- rentally inherited alleles, whereas the other parental allele is silenced by epigenetic mechanisms in a parent- of-origin–specific manner. The parental specificity of the active allele and silenced allele has been faithfully maintained throughout generations. To establish these parental imprints, the germ cells must first lose their inherited maternal and paternal imprints, and the pa- rental imprints must then be reestablished in an allele- specific manner during gamete formation (55, 56). Maternal DNA methylation imprints are established during oogenesis at different time points, depending on the imprinted gene loci, whereas paternal imprints are established during spermatogonial differentiation in the adult testis (57). Once established these epigeneticmarks are able to resist postfertilization global epigenetic reprogramming in the preimplantation embryo through the interaction of the chromatin and DNA-modifying factors zinc finger protein (ZFP)-57 with tripartite motif containing (TRIM)-28, which are attracted tomethylated imprinting control regions (58), or by specific factors, such as DPPA3, that prevent DNA demethylation by binding H3K9me2 and blocking TET3 activity (23). Be- cause of the selective nature of epigenetic reprogram- ming in the preimplantation embryo, inheritance of parental imprints by the new embryo is permissive.
Since the imprinted regions are able to resist the second wave of reprogramming, errors that may occur during the first wave of erasure of parental imprints are maintained in the embryo. Several disorders, such as Beckwith-Wiedemann, Prader-Willi, and Angelman syndromes, are caused by loss of imprinting that results in biallelic expression of the respective imprinted gene. Although these imprintingdefectsmay also be caused by spontaneous epimutations, Buiting et al. (59) reported that loss of imprinting in humans may be the result of a failure to erase the parental imprint. In their study, im- printing defects in a subset of patients with Angelman syndrome occurred on the chromosome inherited from the maternal grandparents, whereas, in a subset of pa- tients with Prader-Willi syndrome, the imprinting defect occurred at the chromosome inherited from the paternal grandmother. While incomplete erasure of the parental imprint may explain some of these phenomena, the observed imprinting defects may also have occurred after the erasure of parental imprints or could result from the patient’s genetic background (59).
REPETITIVE RETROTRANSPOSONS
Maintaining genomic stability is vital for mammalian survival, and several diseases are a consequence of the inability to maintain genomic stability. For example, can- cer is associated with site-specific hypermethylation of CpG islands at promoters and global DNA hypo- methylation at repetitive and satellite regions, such as retrotransposons (60–62). One of the best-studied long terminal repeat (LTR) retrotransposons in mice is the IAP element. IAPs are retroviruslike repetitive DNA elements that possess an LTR region that functions as a promoter. These IAP elements have been suggested to provide a potential pathway of epigenetic inheritance. They are un- der the control of DNA methyltransferase 1 (DNMT1), as transcript levels are elevated in mouse embryos that are DNMT1deficient (63). CpG islands located close to an IAP showed consistently high methylation levels across all developmental stages (64), and methylation of the LTR sequences of most of the IAP element copies in themouse genome persisted through the wave of demethylation that occurs in the preimplementation embryo. A significant fraction of these IAP genomes remained essentially unreprogrammed, even in PGCs (27, 65, 66).
Because of the ability of IAPs to resist the secondwave of reprogramming, IAPs are a potential way of epigenetic inheritance in mammals, and several studies have in- vestigated this in mice. IAPs were reported to be essential in thevariablemethylationaffecting the inheritanceof coat color and tail length in Agouti viable yellow and Axin- fusedalleles inmice (66, 67), andmethylationof theAgouti viable yellow gene in offspring can be modulated by the availability of methyl donors in the maternal diet (68). In utero exposure to methyl donors by the F1 generation in pseudoagouti mice resulted in F2 generation mice with pseudoagouti phenotypes (69). Supplemented mice were more variable in their methylation levels, with the highest variation in mice that were supplemented over several
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subsequent generations. Supplementation also affected the offspring’s disease susceptibility: supplemented off- spring were protected from developing obesity and di- abetes mellitus (70). It is important to note, however, that inheritance of these traits by subsequent and unexposed
generations has not been shown. Also, these mouse ex- periments were performed with inbred mouse strains, which may differ in their ability to reprogram epige- netic marks at IAPs after fertilization (67), and studies performed in one inbred mouse strain may not be
Figure 1. Epigenetic inheritance via the female and male germ line. If a gestating mother (F0, blue) is exposed to environmental stressors, her fetus (green) and its already developing germ line (red) are also directly exposed. As a result, phenotypes observed up to the F2 generation (red) may result from the grandmother’s experience. The F3 generation (yellow) is the first generation that has not been exposed to these environmental stressors, thus phenotypes observed in this generation could represent transgenerational epigenetic inheritance. If inheritance via the male or the maternal germ line before gestation is investigated, environmental stressors may affect the F0 generation (blue) and the developing germ line (red). As a result, the first generation that could represent transgenerational epigenetic inheritance is F2 (yellow).
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reproducible in other strains. Thus, genetic variation may be an alternative explanation for these phenomena rather than epigenetic inheritance. Moreover, the resistance of IAPs to demethylation during development may be a protective trait that prevents IAP retrotransposition, which may induce mutations (65). Thus, the maintenance of DNA methylation patterns may be a bystander rather than the driver, and it is an exceptional situation, as it does not occur on a genome-wide level.
Even though a large portion of the human genome is composed of transposable elements, a similar mecha- nism has not been identified in humans. However, trans- posable elements in humans are also highly methylated (71) and in a recent study, Tang et al. (72) reported that some retrotransposon-associated and single-copy regions in the human genome resist DNA demethylation. As a result, it is possible that factors affecting the degree of methylation cause variable gene expression in humans similar to that in mice.
RNA-DEPENDENT PROCESSES
Epigenetic inheritance may also be mediated by non- coding RNAs (ncRNAs), such as microRNA (miRNA) or long noncoding RNA (lnRNA), and RNA-dependent processes may contribute to the transmission of acquired traits in mammals. ncRNAs have key functions during early development; they control embryonic gene expres- sion, promote developmental transitions, and maintain developmental states (73).
Animal studies suggest that initial inductions resulting in a modification of the early embryonic genome to miRNAsmaybe sufficient to induce aheritablephenotype mediated through miRNAs. Mouse experiments have shown that stress before breeding affects the expression profiles in spermmiRNA and the responsiveness of stress by the offspring (74, 75). However, these alterations are present only in sperm of the F1 generation and not in later generations. Two other studies suggested that an initial induction involving a modification of the expression of critical miRNAs could be inherited both paternally and maternally by the next-generation offspring and could affect the offspring’s phenotype in mice (76, 77). Both studies found specific miRNA sequences in the sperm of the affected animals, whichwas supported by an increase in transcription in the study by Rassoulzadegan et al. (76). Wagner et al. (77) reported that this phenotype could even be transmitted for at least 3 generations. Another study by Padmanabhan et al. (78), reported that aMtrr deficiency in grandparents and parents, leading to a defect in folate metabolism, resulted in epigenetic effects on the daugh- ter’s maternal environment and their gametes, leading to congenital abnormalities. An effect of this Mtrr mutation was foundup to5generations in thewild-typeoffspring. It remains unclear which mechanism underlies this obser- vation, but it may be epigenetic inheritance, even though other possibilities cannot be excluded. For example, the initial mutation in the gene may lead to a perturbed reg- ulation of the nucleotide biosynthesis pathway that may result in deficiencies in DNA repair mechanisms and
potentially genetic mutations (79). Also, the epigenetic mark underlying the stability of the modified phenotypes observed in these studies and the exact role of themiRNAs has yet to be elucidated.
To our knowledge, no data are currently available on the potential role of lnRNAs in transgenerational epige- netic inheritance.
In human sperm, miRNA expression profiles differed between smoking and nonsmoking volunteers (80), but it remains unknown whether these miRNA profiles are maintained during early embryogenesis. In a study on human parent–offspring triads, regulatory scores of most miRNAs correlated between parents and offspring, sug- gestingapossibleheritabilityofmiRNAs(81).However, in humans, consistency in miRNA profiles across subsequent generations has not been reported, nor is there any other proof of miRNA-induced epigenetic inheritance to date.
HISTONE RETENTION
Histones are small proteins that constitute major building blocks of the chromatin structure; they have a positively charged central fold domain and terminal tails. The tails are crucial for normal function of cellular processes, as they are targets for posttranslational modifications, such as acetylation, methylation, phosphorylation, and ubiquiti- nation.Anegative chargeof thehistone tailwill result inan open chromatin structure, allowing access to the tran- scription machinery, whereas positively charged histone tails provide the ability to fold the chromatin, protecting it from transcription. Histones have been reported to be an important factor in early life development, as embryos deficient of certain histone methyltransferases display se- vere growth retardation and early lethality (82, 83).
Todate, little support is available for a role ofhistones in the process of transgenerational epigenetic inheritance. Studies in both mice and humans include only early stage embryos, and thus it remains unclear what the impact of these modifications is for the offspring in later stages of development.
In mice, specific histone modifications were found to undergo reprogramming during early embryo develop- ment. Hyperacetylated histone H4, Me(Arg17)[3H], and Me(Arg3)H4 marks were removed during the metaphase in eggs and early embryos, whereas the histone marks Me(Lys9)[3H], Me(Lys4)[3H], and Ph(Ser1)H4/H2A were reported to be stable until at least the blastocyst stage of development (84).
A study with human sperm suggested that epige- netic inheritance may transit through an incomplete replacement of histones by protamines during game- togenesis (85). In this study, correlations were observed between H3K4me in sperm and early expression in the embryo. A human embryo study suggested that con- stitutive heterochromatin marks in the embryo are transmitted and retained from human spermatozoa (86). However, it remains to be clarified whether these histone marks are maintained during later embryonic development and whether they can be propagated into subsequent generations.
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DISCUSSION
Transgenerational epigenetic inheritance is a topic of great interest as the potential relevance of epigenetics for DOHaD is being scrutinized. However, many questions remain. If transgenerational inheritance is present in the formof incomplete erasure, it remainsuncertainwhether it is an error or there is an evolutionary advantage to main- tainingepigeneticmarks reflecting theparents’ experience.
It has been observed in animal experiments and in ep- idemiologic studies inhumans that the impact ofnutrition, smoking, irradiation, and even traumatic exposures in the parents andgrandparentsmayaffect the (grand)children’s phenotype or risk of diseases, and similarities in the epi- genetic profile between parent and offspring have been found (39–43, 46–52, 87–91). These observations may be caused by intrauterine exposures, germ-line–mediated transmission of phenotypic traits through genetic muta- tions,mutations in theDNArepairmechanisms, orgenetic mutations in epigenetic modifiers, rather than to the con- tinuity of epigenetic marks between generations. More- over, a shared environment may explain parental and sometimes even grandparental, similarities in the epige- netic profile, rather than transgenerational epigenetic inheritance.
A condition for transgenerational epigenetic inheri- tance is that the epigenetic mark and the associated phe- notype are maintained for at least 4 generations in a gestating female and for at least 3 generations if pre- gestational exposures or inheritance via themale germ line are investigated (53, 54). Few studies have considered the maintenance of epigenetic marks for these durations. Wagner et al. (77) observed in a mouse experiment that miRNAsweremaintained over 3 generations of offspring, and a study by Padmanabhan et al. (78) in mice suggested that an Mtrr mutation may impact epigenetic inheritance for up to 5 generations. Nonetheless, these studies were performed in animals that were genetically inbred, and it remains unclear whether these results are reproducible in other mouse strains.
The most convincing examples of potential pathways of transgenerational epigenetic inheritance come from mouse studies suggesting resistance to epigenetic reprogramming by repetitive retrotransposons or in- heritanceofmiRNAprofiles.Differences in the epigenome between humans and mice do not permit direct inference to humans (92, 93), and to date there is no evidence of transgenerational epigenetic inheritance in humans, ex- cept for the parent-of-origin specificity of genomic im- printing. Some histones have been reported to be stably inherited from the parents to the offspring during the first phases of embryonic development; correlations in the regulatory effect scores of miRNAs were observed be- tween parents and offspring; and in imprinting disorders, some of the imprinting defect in humansmay be the result of a failure to erase the parental imprint. However, in all these examples, it remains unclear whether those marks are preserved during later stages of development and in subsequent generations and other possible explanations for the observed effects cannot be excluded, such as the influence of genetic background. The genetic contribution
toDNAmethylationwas investigatedbyGertz et al. (94) in 3 humangenerations. They reported thatmost variation in DNAmethylation in the genome can be explained by ge- notype and that thegenetic influence exceeds the influence of imprinting on genome-wide methylation levels. Their data are further supported by twin studies, where evi- dence was found for within-pair epigenetic variability, including bothmethylation and gene expression analyses, in multiple tissues at birth (95–97). Methylation and gene expression differences withinmonozygotic (MZ) twin pairs were observed to be smaller than those observed for dizy- gotic (DZ) twins (95, 96), suggesting a genetic contribution tomethylationandgeneexpressionprofiles.MZdichorionic twins, each with their own placenta, displayed greater within-pair expression discordance than did MZ mono- chorionic twinswhosharedaplacenta (97), likely influenced by the intrauterine environment. These observations are in line with the concept that perceived inheritance of DNA methylation is driven by genetics and intrauterine exposure rather than transgenerational epigenetic inheritance.
FUTURE PERSPECTIVE
The study of transgenerational epigenetic inheritance in humans is more complex than in animals for several reasons. First, because transgenerational epigenetic in- heritance has to be maintained for several generations, longitudinal multigenerational studies are required with biospecimens available for 3 to 4 generations. To date, no such studies have been conducted. Second, studies in hu- mans are characterized by individual variation, stochastic differences, and ethical restrictions and thus differ pro- foundly from the controlled environment of animal stud- ies. Last, the heterozygosity of the human population makes it difficult to distinguish between genetics and epigenetics. Only when individuals are truly genetically identical and exhibit a range of phenotypes that are heri- tablemay thesebe attributed toepigenetic variation.These factors make it hard to study transgenerational epigenetic inheritance and its potential players in humans.
To fully understand transgenerational epigenetic in- heritance, the influence of intrauterine exposures and a shared postnatal environment on the epigenetic signature has to be studied in greater detail to enable a clear dis- tinction between these exposures and transgenerational epigenetic inheritance. Future studies may focus on un- derstanding how epigenetic marks during early life de- velopmentare established, inaddition to identifyepigenetic marks that are maintained over subsequent generations. Shedding light on these processes may help to understand whether, and how, parental epigenetic marks influence offspring’s health and disease susceptibility through transgenerational epigenetic inheritance and intrauterine exposures.
CONCLUSIONS
Several processes that may be part of intergenerational epigenetic inheritance have been identified in mice.
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However, much uncertainty remains as to whether these processes are truly epigenetically inherited or are influ- enced by other factors, such as intrauterine exposures and genetics, andwhether these epigenetic marks can be maintained over several subsequent generations. As a result, proof of principle of a widespread transgenera- tional epigenetic inheritance is lacking to date. Because of differences in the epigenome between mice and hu- mans and the limited number of studies performed in humans, the concept of transgenerational epigenetic in- heritance in humans remains equivocal.
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Received for publication December 18, 2015. Accepted for publication March 21, 2016.
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