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Transgenerational epigenetic inheritance: how important is it?

Transgenerational epigenetic inheritance: how important is it?

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How much transgenerational epigeneticinheritance takes place? 
Ueli Grossniklaus.
To give a short answerfirst: I do not think we know how widespreadtransgenerational epigenetic inheritance isin any organism. Given this uncertainty, itis surprising how much attention this ques-tion has attracted in recent years, both in thepopular press and in the scientific literature(for example, see
). In principle,many inherited traits could have an epige-netic basis, as one cannot easily distinguishwhether a phenotype is due to genetic orepigenetic variation without a detailedmolecular analysis. It is also possible thatepigenetically controlled traits are rare. Butgiven the rapid advance of epigenomics,I am sure that we will get a much betterunderstanding of the contribution of genetic versus epigenetic variation to phenotypes inthe near future.To provide a more profound answer,however, I will have to define what I under-stand by ‘transgenerational’ and epigenetic’,given that the use of both terms varieswidely. A popular definition of epigeneticsstates that it concerns the study of mitoti-cally and/or meiotically heritable changes ingene expression that occur without a changein DNA sequence
. Under this definition,epigenetic regulation has a role at two levels.First, it is involved in development, leadingto the specification of cells and assuring thefaithful inheritance of their differentiatedstate over mitotic cell divisions. Second,epigenetic states can be inherited meiotically,from one generation to the next, and this isthe focus here.While some biologists consider all effectsthat concern both parents and offspringto be transgenerational, I would like todistinguish transgenerational effects fromparental and — depending on the system— grandparental effects. In addition to con-tributing their DNA, parents can influencetheir offspring in many ways: for example,by contributing bioactive molecules in theegg and sperm cytoplasm, by providingnutrients and hormonal informationduring embryogenesis and by provisioningand taking care of offspring after birth.is modulated by the animal’s diet
. Thespecific dietary conditions in which apregnant female is raised can changethe inheritance pattern over two genera-tions, but this change gets lost in the thirdgeneration
. Thus, while this specific dietleads to parental and grandparental effects,the induced epigenetic changes are nottransgenerationally inherited.Often ignored in studies of transgen-erational inheritance, parental effectscan also occur in plants. The conditionof the mother plant has a strong effect onthe seeds it produces with respect to, forinstance, nutrient provisioning. At thetime of dispersal, the offspring itself is stillsurrounded by the maternal tissues of theseed coat, and these tissues play a crucialpart in the hormonal regulation of seedgermination. Thus, in plants too, parentaleffects can have a strong effect on the nextgeneration
and may confound studies of epigenetic inheritance
.In many experimental systems, thereis clear evidence that silenced transgenesare stably inherited over several genera-tions. This is different for natural epigenetic variants that cause a phenotype (that is,epialleles). In mammals, only very few — sometimes controversial — cases of meitotically inherited epialleles have beenreported, mostly with a variable degree of inheritance
. By contrast, there are severalwell-studied examples of stably inher-ited epialleles in plants
, of which I willmention just two. The first example wasreported in toadflax (
Linaria vulgaris
), inwhich a variant with radially symmetricflowers, rather than the typical bilaterally symmetric ones, was already described by Lineus nearly 200 years ago. This pheno-type is not caused by a mutation but by DNA methylation of the
gene,which controls the formation of dorsal pet-als
. Another example of a natural epiallelecauses the
Colourless non-ripening 
pheno-type in tomatoes (
Solanum lycopersicum
.In both cases, no differences in DNAsequence could be detected at the affectedloci, strongly indicating that the mutantphenotypes had an epigenetic nature.
Bill Kelly.
Research in
has illustrated numerous instancesof transgenerational epigenetic inheritance.Examples of epigenomic patterns that arestably inherited include those that have beenobserved in other species (for example,heterochromatin and centromeric histonepatterns) but also epigenomic patterns thatare established by gene activity.
Transgenerational epigeneticinheritance: how important is it?
Ueli Grossniklaus, Bill Kelly, Anne C. Ferguson-Smith, Marcus Pembrey and Susan Lindquist 
Abstract | Much attention has been given to the idea of transgenerationalepigenetic inheritance, but fundamental questions remain regarding how muchtakes place and the impact that this might have on organisms. We asked fiveleading researchers in this area — working on a range of model organisms and inhuman disease — for their views on these topics. Their responses highlight themixture of excitement and caution that surrounds transgenerational epigeneticinheritance and the wide gulf between species in terms of our knowledge of themechanisms that may be involved.
when consideringenvironmentally induced effects... an epigenetic basis can beinferred only if they last overmultiple generations
Many of these parental (and sometimesgrandparental) effects will not have anepigenetic basis. This is particularly impor-tant when considering environmentally induced effects, for which an epigeneticbasis can be inferred only if they last overmultiple generations. In a pregnant mam-mal, for instance, not only are the motherand fetus exposed to the same environ-mental influences but so are the fetus’s pri-mordial germ cells, which will eventually produce the grandchildren. For instance,expression of the methylation-sensitive,metastable
agouti viable yellow (
) allele,which determines mouse coat colour andshows meiotic epigenetic inheritance
MARCH 2013
© 2013 Macmillan Publishers Limited. All rights reserved
The heritable silencing of repetitiveDNA elements — the heterochromaticcompartment in many genomes — is clearly transgenerational and involves epigeneticmechanisms. Recent work from multiplelaboratories has shown that the highly con-served PIWI-interacting RNA
(piRNA) sys-tem (which involves a specific class of small,non-coding RNAs) acts in the
C. elegans
germline as a sort of adaptive genome immunity system, in which an enormous diversity of RNA sequences can potentially be recognizedand targeted for assault (for example, see
). The initiating response is guidedby piRNAs, from which a secondary systemrefines and amplifies the response, narrowingthe target specificity and increasing the effi-ciency. Importantly, almost any sequence canbe identified — not just repetitive elements— and thus endogenous loci can also be tar-geted by this mechanism in an autoimmuneresponse. Targeting of ‘self’ sequences appearsto be prevented both by selection against self-targeting piRNAs and by a counteracting pro-cess using RNAs that are generated throughnormal germ cell transcripts (that is, self RNAs). Successful and heritable repressionis achieved though the assembly of repres-sive chromatin, which can be stable for many generations. None of this multi-generationalrepression involves a genetic change in thetargeted sequences.These observations represent the repres-sive side of transgenerational epigeneticinheritance: there is also the opportunity forheritable activation of genes. Transcriptionin the germ line has the capability not only to generate self RNAs to prevent piRNAtargeting but also to alter chromatin by mobilizing nucleosomes and producingmodified chromatin in its wake.
C. elegans
 embryonic chromatin carries an epigeneticmemory of transcription that last occurredin the parental germ cells
. This memory includes covalent modifications (histone H3methylation isoforms) that are associatedwith ‘open’ chromatin and added to genesduring transcription in the parent. The meth-ylation patterns are subsequently maintainedin the embryo by methyltransferases that canoperate independently of transcription. Thepresence of these particular marks can beantagonistic to other repressive histone H3methylation marks. Thus, transcription-coupled establishment and maintenance of histone marks in germ cell chromatin, perhapscoupled with the insertion of histone variants,can prevent intrusion of repressive chromatinassembly into genes, and this appears to berequired to promote the proper activation of these genes in the next generation
.Indeed, the clearest example of transgen-erational epigenetic inheritance in many organisms, centromeric chromatin, alsoappears to be guided by transcription in
C. elegans
, albeit negatively. The heritably stable positions of centromeres are guidedby incorporation of the centromere-specifichistone H3 variant CENPA (also knownas CenH3). CENPA incorporation, whichproduces the
C. elegans
holocentromere,occurs where transcription activity is absentin parental germ cells; that is, transcriptionprevents stable CENPA placement in paren-tal germ cell chromatin, and this heritably templates stable centromeric chromatinassembly in the offspring
.Therefore, an answer to ‘how muchtransgenerational inheritance takes place’in
C. elegans
may be that this seems tobe a guiding mechanism for centromeredesignation and much of the germlinetranscriptome in this organism. It is worthnoting that most of the factors that guidethese epigenetic processes in
C. elegans
haveorthologues in most eukaryotes, so it iscertainly plausible that these routes to epi-genetic inheritance exist in many organisms.
Anne C. Ferguson-Smith.
The impactof the environment has been observed toextend over multiple generations in bothhuman populations and animal models
,suggesting transgenerational epigeneticeffects. However, a defined mechanism forsuch inheritance is missing.It is clear that epigenetics can conferstable, heritable, functional genomic con-figurations within somatic lineages
.However, one of the most importantproperties of this epigenetic memory is itsdynamic nature and particularly its ability to be erased
. This erasure happens both in
The contributors
Ueli Grossniklaus is Professor of Plant Developmental Genetics at the Institute of Plant Biology of the University of Zürich, Switzerland. From 2006 to 2011, he was President of the Zürich–BaselPlant Science Center and is currently Co‑leader of the University Research Priority Program‘Evolution in Action’. His research focuses on the genetic and molecular basis of plant reproduction.He made seminal discoveries on the mechanisms that epigenetically control seed developmentboth through maternally deposited factors and by genomic imprinting, a paradigm for epigeneticregulation. Over the past years, ecological and evolutionary aspects have been included in hisresearch with the goal of gaining a better understanding of the role of epigenetics in adaptation.Bill Kelly is the Director of the Genetics and Molecular Biology Program and an associateprofessor in the Biology Department at Emory University, Atlanta, Georgia, USA. His research hasfocused on epigenetic regulation of germ cell specification, maintenance and differentiation,and epigenetic memory and reprogramming using
Caenorhabditis elegans
as a model system.His research has been supported by the US National Institutes of General Medical Sciences in theNational Institutes of Health.Anne C. Ferguson‑Smith is Professor of Developmental Genetics in the Department of Physiology,Development and Neuroscience at the University of Cambridge, UK. For the past two decades,her team has studied genomic imprinting in development and disease and the epigeneticcontrol of genome function in a wider context. Her current research focuses on three themes:stem cells and the epigenetic programme, functional epigenomics, and developmentenvironment and disease.Marcus Pembrey is Emeritus Professor of Paediatric Genetics at the Institute of Child Health,University College London, UK, and a visiting professor of Paediatric Genetics at the University of Bristol, UK. Marcus was previously an honorary consultant clinical geneticist at Great OrmondStreet Hospital for Children, London, UK. In 1988, he helped Jean Golding to establish the AvonLongitudinal Study of Parents and Children (ALSPAC) in Bristol, UK, and served as its Directorof Genetics until 2005. Interested in unusual inheritance patterns, he studied fragile X andAngelman syndrome during 1980–1990 and then moved onto study epigenetics more generally.His current research focus is on environmental epigenomics and human transgenerationalresponses.Susan Lindquist has shown that the forces governing protein folding can have a profound andunexpected impact on evolution and human disease. She discovered the disaggregating abilitiesof heat‑shock proteins, identified prions as conduits of protein‑based inheritance and pioneeredthe use of yeast as a model system to study complex diseases and to develop novel therapeuticstrategies. She found that protein‑folding processes buffer and release the effects of accumulatedgenetic variation, providing the first plausible explanation for rapid bursts of evolution andestablished that the heat‑shock response has a key role in the evolution of fungal drug resistanceand tumour progression.
MARCH 2013
© 2013 Macmillan Publishers Limited. All rights reserved
the germ line and early in pre-implantationmammalian development and is followedby the establishment of new functionalchromatin configurations. If true epigeneticinheritance is to occur, then under particu-lar circumstances some epigenetic markswould be expected to be completely or partially resistant to both of thesereprogramming events
.At unique sequences, strong evidencethat DNA methylation is a transgeneration-ally transmitted heritable epigenetic mark remains elusive. However, it may be nocoincidence that many cases of transgen-erational epigenetic inheritance involverepeat sequences
. Epigenetic silencingmechanisms are likely to have evolved, atleast in part, to repress repetitive elementsthat have the potential to activate anddestabilize the genome and/or to change theexpression of adjacent genes
. Hence,these elements are a target for the epige-netic machinery in somatic tissues andespecially in the germ line. In particular,DNA methylation of repetitive retrotrans-posons has provided one of the best modelsof transgenerational epigenetic inheritance.For example, the
allele in mice is aninsertion of a long terminal repeat (LTR)retrotransposon called an intracisternalA-type particle (IAP) upstream of theagouti coat colour gene. Trangenerationalinheritance of coat colour occurs, whichdepends on the extent of methylation of this element
. In addition, methylationof 
in offspring can be modulated by maternal diet
. Importantly, however, theextent to which these effects can be inher-ited by subsequent generations remains tobe clarified.Perhaps even more compelling evi-dence for repeat sequences contributing totransgenerational epigenetic inheritancehas come from data showing that IAPs may be more refractory than other sequencesto germline and pre-implantation DNAdemethylation
. These elementstherefore have the properties required of sequences for which the epigenetic state canpersist transgenerationally and can have animpact on the expression of neighbouringgenes. Environmental modulation of theefficiency of repeat sequence reprogram-ming may contribute to variations in theexpression of associated genes in offspringand may lead to phenotypic outcomes.In addition to the potential contri-bution of IAPs, other mechanisms fortransgenerational epigenetic inheritancemay exist, and small RNA-mediatedprocesses, such as those described abovein other organisms
, may be goodcandidates for involvement
. Germlinemodulation by small RNAs in mam-mals has particularly been describedin the male acting on epigenetic statesand post-transcriptionall
. Defectsin this process might have an impact onthe behaviour of genes after fertilization.Post-transcriptional regulation induced by small RNAs experimentally injected intogerm cells and newly fertilized eggs hasbeen observed, affecting post-fertilizationphenotypes
. However, how these effectsmay be propagated into subsequentgenerations remains a mystery.tissue-specific changes in expression, it isnot clear whether the impact on phenotypewas a primary or a secondary effect.Perhaps the strongest argument againsttransgenerational epigenetic inheritancesurrounds the challenge of ruling outgenetic effects underlying the phenotype inoffspring. The impact of genetic variationon epigenetic state is recognized but is only beginning to be understood and quantified
.While tissue-specific differences in epige-netic states within individuals are knownto outnumber inter-individual epigeneticdifferences within the same tissue
, achange in epigenetic state between parentand offspring might be caused by genetic variants. As human epidemiologicalstudies are carried out on populationsof mixed genetic backgrounds, and alsobecause epigenotype–phenotype analysescan involve small sample sizes, cautionin the interpretation of such studies hasbeen encouraged
. The relative contribu-tions of genetic and epigenetic variation totransgenerational epigenetic inheritancein mammals will be better understoodthrough the use of isogenic strains in animalstudies and the quantitative integration of whole-genome sequence information intoepigenotype–phenotype analyses on largesample sizes.
Marcus Pembrey.
Molecular evidence fortransgenerational epigenetic inheritancein humans is limited, but I suspect that it iscommonplace. Transgenerational epigeneticinheritance is the best candidate mechanismto explain the male-line transgenerationaleffects that are now being demonstratedwithin cohort studies capable of dealingwith many social and other confound-ers
. If these observations are statisti-cally sound and cannot be explained by genetic or cultural inheritance, then this istransgenerational epigenetic inheritance inits broadest sense.Humans have imprinted genes (see theCatalogue of Parent of Origin Effectsweb-site), and genomic imprinting establishesthe principle of transgenerational epigeneticinheritance: the gene is active or silentdepending on epigenetic marks placed inthe parental generation that survive eras-ure as they pass to the offspring
. Thisparent-of-origin-dependent gene expressionreflects a robust, evolved response to differ-ences in cellular conditions between egg andsperm formation. Note that this responsedepends on the DNA sequence of therelevant imprinting control centre,microdeletions of which cause imprinting
it may be no coincidence thatmany cases of transgenerationalepigenetic inheritance involverepeat sequences
In the search for mechanisms underly-ing transgenerational epigenetic inherit-ance, some emphasis has been placed ongenomic imprinting, which is the normalprocess that causes genes to be expressedaccording to their parental origin. Imprintsin mice are regulated by DNA methyla-tion that is established in the germ line butoccurs at different loci in the developingsperm and oocyte. What makes imprintedgenes such good candidate mediators of transgenerational epigenetic inheritance?First, they are exquisitely dependent onepigenetic mechanisms for their parent-of-origin-specific expression and dosage
.Second, imprinted genes function in path-ways that contribute to phenotypes that arecurrently most associated with transgen-erational epigenetic effects: growth,metabolism, behaviour and environmentaladaptations
. Perhaps most importantly,imprints are by definition resistant to thesecond wave of reprogramming that occursin the pre-implantation embryo
. Hence,all that might be required for a defectiveimprint to have a transgenerational impactis compromised germline reprogrammingof methylation imprints.Recently, experiments have been con-ducted to test whether imprinted genes asa class are more or less environmentally modulated compared with other genesin a mouse model of intergenerationalphenotypic inheritance
. Imprinted genesas a group showed no marked differencefrom randomly selected genes
. Whilesome individual imprinted genes showed
MARCH 2013
© 2013 Macmillan Publishers Limited. All rights reserved

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