When epigenetic errors—or epimuta- tions—activate or inactivate a critical gene, they may cause disease. An epi- phenomenon in multicellular eukaryotes: it. The roles of cohesins in mitosis, meiosis, and human health and disease. Methods Mol Biol Epigenetics in disease: leader or follower? Epigenetics Epigenetics principles and practice. Dig Dis. ;–5. Martin DIK, Cropley JE, Suter CM. Epigenetics in disease: leader or follower? Epigenetics.

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Skip to main content. Log In Sign Up. Cropley2 and Catherine M. Epigenetic phe- or silent state. The variety of molecules nomena typically involve stable silencing involved, and the requirement for active of a gene or a gene regulatory element, or maintenance of epigenetic states, creates an equilibrium between silent and active the potential for errors on a large scale.

When epigenetic errors—or epimuta- tions—activate or inactivate a critical gene, they may cause disease. An epi- phenomenon in multicellular eukaryotes: Epigenetic mech- But the stochastic and reversible nature anisms and transcriptional regulation are of folliwer phenomena predicts that not distinct systems; they interact to pro- epimutations are likely to be mosaic and duce probabilistic patterns of gene activity inherited in a non-Mendelian manner; and eipgenetics.

We animals do not in gen- inheritance. Much phenotypic variation eral maintain mechanisms that mutate our and common disease might be explained DNA immunoglobulin genes in lympho- by epigenetic variation and aberration. But we do disease are at present limited, but this possess complex and constitutive epigen- may reflect only the difficulty in distin- etic mechanisms that silence portions of guishing causal epigenetic aberrations our genome, and keep them silent.

Errors from those that are merely consequences in these mechanisms can result in aberrant Key words: The rapidly can occur at any time. When an error DNA methylation developing molecular characterization of occurs late in development or cell differ- Submitted: Suter; answers have the potential to transform The epigenome mediates genome Email: This applies to the be the clearest examples of epigenetic can drive neoplastic progression, and per- epigenomes of germline cells, which disease.

Here we when neither allele is active. Aberrations A Prototype for Epigenetic discuss how epigenetic aberrations may of dieease are examples of epimuta- Disease Causality result in disease, how epigenetic mosa- tion and, in some cases they may be pure icism can modulate disease risk, and how epimutations i.

In most cases the cause provides a clear example in which epi- environmental agents. In some cases, how- a disease syndrome hereditary non- ever, there appears to be no responsible polyposis colorectal cancer, HNPCC; We define an epigenetic disease as one genetic lesion; instead, there is an appar- reviewed in ref.

Our search for caused by a stable alteration in the epigen- ently random failure of accurate resetting germline epimutations was prompted by etic state of a gene epimutation without dsiease one of the alleles in the parental germ the hypothesis that large portions of the any contributory genetic mutation. This cells, causing one allele to be inappropri- genome, particularly repeat elements, are definition excludes the many diseases in ately either active or silent.

In cancer We reasoned that because active mecha- nisms are required to establish and main- tain epigenetic silencing, the presence of a Donotdi str ibut e. Genetic diseases are caused by DNA sequence mutations that perturb or abolish the function of a gene.

Recurrent epi- inactivating genetic mutations. If the epi- ingless. The epigenome is made up of a mutations that silence tumor suppressor mutation were retained in the somatic cells very large and incompletely character- genes implicate epigenetic mechanisms in derived from the tollower cell in which it ized variety of molecules, rather than a neoplastic progression, but DNA muta- arose, then all somatic cells would carry single, stable and faithfully inherited mol- tions are also an invariant feature of can- an inactive copy of the gene.

Although ecule like DNA. Changes in the molecu- cer cells. It is relatively simple to imagine germline epimutations might be common, lar composition of the epigenome underlie scenarios in which DNA mutations in in most cases only one allele would be development, cell differentiation and gene genes responsible for epigenetic stability affected and no phenotype would be evi- regulation, and thus any condition that could cause the epigenetic aberrations, dent; inheritance might occur, but prob- alters the cellular makeup of a tissue, or and almost as easy to suppose that certain ably in non-Mendelian patterns.


Tumor gene expression within a cell type, will be epimutations drive genetic instability. But suppressors are attractive candidates for leder with changes in the epigenome. Establishment epigenetic defects, and it is not possible to somatic loss or inactivation of folpower unaf- of a causal connection between genetic establish what began the process.

This strategy laws, making it very difficult to assign an Germline mutations in tumor suppressor identified two individuals with apparent epigenetic cause to disease. Epigenetic mosa- tein MLH1. Appearance of an epimutation after icism could create the broad spectrum of acteristics epigenetkcs HNPCC, a disease caused the first zygotic cell division would lead disease penetrance, and complex patterns by genetic mutation of MLH1 or other to epigenetic folliwer, but mosaicism of inheritance, that are features of com- mismatch repair genes.

The lleader and dis- which has proven elusive.

Epigenetics in disease: leader or follower?

We have tribution of affected cells in the adult will Neoplastic progression involves clonal argued that a genetic basis for these epi- depend upon the timing of the epimuta- expansion, so that a defect present in rare mutations is extremely unlikely. But what cases of MLH1 germline epimutation have affected cell. We suggest that most epi- of diseases that do not involve expansion now been reported; these include two mutations are inborn, and that most will of the affected cells?

If there are non- in which the epimutation appears to have exhibit some degree of mosaicism. The to occur, a second hit in the same cell is evoke a phenotype. Individuals with lower germline instability of the MLH1 epimu- required. The chance of this occurring will burdens may present with phenotypes at tation, and the sizable number of reported be higher in individuals harboring a larger the borderline of normal.

Consider, for cases, raise the interesting possibility that proportion of cells carrying the epimuta- example, familial hypercholesterolemia, germline epimutations in MLH1 hap- tion. We speculate that low-level epigenetic mosaicism for epimu- tation in many genes is common: Alternatively, a smaller number of affected cells could have a disproportion- Donotdi str ibut The case of MLH1 demonstrates that e. This hypothesis may be contrasted with ately large effect on phenotype if they reside in a relevant organ in the case of LDL-R, the liver.

Pr, cases may Mosaicism is a common feature of epigen- often be present in somatic cells at birth. Could some mosaicism is present, because mosaicism individuals carry epimutations in only a Epimutation Beyond Cancer should lead to reduced disease penetrance. There is no reason to suppose that germ- Environmental Influence Individuals with a germline epimu- line epimutation is confined to MLH1, on Epigenetic Disease?

On the other of their somatic cells, presumably as the hand, there is no peigenetics clear example of The MLH1 germline epimutations might result of an epigenetic error occurring human disease caused by a germline epi- best be considered as epigenetic accidents either in the parental germline or the genetic silencing of a gene although there conditioned by constitutive mechanisms zygote.

But epigenetic silencing mecha- are examples in which a genetic lesion that initiate and maintain epigenetic nisms are constitutively active in multi- predisposes to somatic epimutation. But epigenetic mechanisms are cellular eukaryotes, making it possible While the poor heritability of epimuta- interposed between the genome and the for epimutations to arise throughout the tions means that homozygosity should environment, and mediate responses to lifetime of an individual.

Mistakes may be be extraordinarily rare, there are many environmental signals, so that epigenetic more likely to occur at points when epi- examples of leadwr diseases caused accidents are perhaps a predictable out- genetic marks are set or reset, i.

Donotdi str ibut e. A Agouti viable yellow Avy mice demonstrate epigenetic mosaicism. The epigenetic state of Avy varies widely between mice and be- tween cells of each mouse, so that isogenic littermates display variable expressivity of the associated coat color phenotype, from full yellow left through various degrees of mottling middle to complete agouti right.

The vaguely somitic patterning of the mottled patches suggests that the epigenetic state of Avy is set early in embryonic development. Every gene in every individual may lie on a spectrum of epigenetic mosaicism created by stochastic errors and environmental exposures. Some individuals carry a germline epimutation that affects all of their cells, or most cells if some cells have reverted to normal—their risk of disease is high. Most individuals carry some level of mosaicism for epimutation, whereby only a proportion of cells are affected.


Avy is an instructive model of ectopically expressed. The viable yellow syn- is silent, ASP is expressed in its normal Environmental influence on epigen- drome of yellow coat, obesity, diabetes and restricted pattern and the mice are lean etic states and disease is epitomized by cancer is caused by transcriptional activity with agouti coats Fig.

Epigenetic disease—considered as a phe- genetic disease risk by somatic mosaicism. The epigenome may be most vulnerable nomenon in which aberrant epigenetic The retrotransposon controlling element to environmental influence during embry- states are the primary cause of a disorder— that drives the Avy allele is stochastically onic development, when epigenotypes are remains largely a concept. But the perva- silenced in early development, so that iso- changing and cells are multiplying, so sive influence of epigenetic mechanisms genic mice are mosaic and display a broad that any induced changes may ultimately in eukaryotic biology, and a handful of spectrum of phenotypes.

While much epigenetic variation likely to be silent and methylated ,23,24,26 ture of livestock embryos. The syndrome and aberration may be spontaneous a and so fewer mice have the typical syn- has been linked to epigenetic aberrations result of stochastic errors in constitutive drome of yellow fur, obesity and diabetes.

But ascertain- that the intrauterine environment can these cases seem to involve the sort of pure ing the extent and mechanism of epigen- act on epigenetic states in the developing epimutation that is only a small subset of etic disease presents challenges. Further, there is a progressive the total caseload of imprinting disorders. These data indicate epigenetic inheritance response to environmental stress.

Embryo culture is an extreme stress on an early embryo. More subtle changes to the early a complex and labile set of accretions to DNA, has no established methods for dis- tinguishing causal lesions from those that Donotdi str ibut e.

Epigenetics in disease: leader or follower? – Semantic Scholar

Somatic mosaicism, weak inheritance, natural epigenetic variation and environ- ruption in rats. Based on the link between CpG of particular loci in offspring reviewed an epigenetic state to pathogenesis. Recent methylation and silencing of the ret- in refs. A caveat here is that developments in genome-wide analysis of rotransposon responsible for Avy activity, most reported changes are small, and it epigenetic modifications and their adop- it has been supposed that eepigenetics donors is becoming increasingly clear that there tion into large-scale population studies exert their effect directly by methylation is a substantial degree of epigenetic fillower may see these challenges overcome.

It is more likely, how- tion within populations independent of ever, that their effects are indirect, and environmental or genetic variation, so it References 1.

To be or not to that they act by altering the probability of is likely that few of the studies published be active: Trends Genet ; Inherited epimutation or a haplotypic basis for the propensity to silence? Nat significantly, however, we do not see any variation among individuals, the effects Genet ; Rather, we see many small variations and the causal role of epigenetic variants H, Wood WG, et al. Transcription of antisense RNA leading to gene silencing and methylation as a novel in methylation density both increased in disease, are at present unclear.

Although cause of human genetic disease.

Nat Genet ; and decreasedmany of which occur there is much interest in this subject, and Heritable germline epimutation exhibit stochastic methylation variabil- genetic disease has acquired the status of a of MSH2 in a family with hereditary nonpolyposis colorectal cancer.

Nat Genet ; The exposure to methyl donors thus folk belief in some circles, the confound- 6. In the absence of an obvious tion and somatic mosaicism will make it methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons phenotype, inherent epigenetic variation extremely difficult to establish causality. Mechanisms of imprint dysregulation. DI, Hawkins NJ, et al. Inheritance of a cancer- CpG methylation of a silent controlling element in 8.

Rodriguez-Paredes M, Esteller M. Cancer epigenetics associated MLH1 germ-line epimutation. N Engl J the murine Avy allele is incomplete and unresponsive reaches mainstream oncology. PLoS One ; 9. Mintz B, Illmensee K.

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