Transgenerational epigenetic inheritance

Abstract

What is it? If you thought all heritable traits are written in the DNA sequence, think again! We have come to realize that, at some alleles, the epigenetic state of the DNA can also be inherited. This is indicated by analysis of alleles where the establishment of the epigenetic state is stochastic. As epigenetic modifications influence transcriptional activity, these alleles are variably expressed in a population of individuals. It has been shown that the epigenetic state, and associated phenotype, can be inherited transgenerationally.What is the physical nature of epigenetic modifications? They include DNA methylation and/or covalent modifications of histone proteins. Epigenetic modifications influence gene expression but do not change the DNA sequence, and are mitotically relatively stable.What is variable expressivity? In general, the establishment of epigenetic modifications at mammalian alleles during early development is a predictable process. At some alleles, however, the establishment is stochastic. Once established, the epigenetic state is maintained throughout the life of the individual. So identical alleles can be variably expressed in a population and, importantly, this is not due to genetic or environmental heterogeneity. Such alleles are referred to as ‘metastable epialleles’.How does epigenetic inheritance occur? There is genome-wide epigenetic reprogramming during gametogenesis and early embryogenesis. It was thought this would erase epigenetic modifications acquired during the life of the animal, in order to restore the totipotency of the fertilized egg. But it turns out that sometimes epigenetic modifications at variably expressed alleles are not completely erased, resulting in some memory of the epigenetic state persisting in the next generation.How about an example? The coats of isogenic mice carrying the agouti viable-yellow (Avy) allele vary from completely yellow to the wild-type agouti. Avy has a retrotransposon upstream of the agouti gene. An unmethylated retrotransposon promoter overrides the agouti promoter, resulting in ectopic agouti expression and a yellow coat. A methylated retrotransposon cannot do this, resulting in a wild-type agouti coat. Yellow mothers produce more yellow offspring than agouti mothers, even when all the mice are genetically identical – transgenerational epigenetic inheritance. Transgenerational inheritance of epigenetic states has also been demonstrated in plants, yeast, Drosophila and in mice after transgenesis and nuclear transfer.Isn't parental imprinting also epigenetic inheritance? No! Parental imprinting is the epigenetic silencing of one allele of a gene based on the parent of origin, resulting in monoallelic expression in somatic cells. Epigenetic differences between the two alleles of parentally imprinted genes are completely erased through meiosis and then re-established according to the sex of the animal. For paternally expressed genes, for example, males transmit active alleles, whereas females transmit inactive alleles.What is the difference between transgenerational and mitotic epigenetic inheritance? Epigenetic modifications are propagated through mitotic cell divisions and this is sometimes called epigenetic inheritance. It is important to distinguish mitotic epigenetic inheritance from transgenerational inheritance of epigenetic states through meiotic cell divisions.What is the take-home message? Genotype and environment are not the only determinants of phenotype and DNA is not the sole unit of heredity. It is hard to estimate how widespread epigenetic inheritance is, but such effects seem to be associated with retrotransposon insertions. It is worth noting that almost 9% of the human genome is thought to be of retroviral origin. Studies of transgenerational epigenetic inheritance in humans have been confounded by our extreme genetic and environmental heterogeneity, but it is not inconceivable that some heritable characteristics in humans may in fact have an epigenetic basis.