Epigenetic modifications have effects on phenotype, but they are generally considered to be cleared on passage through the germ line in mammals, so that only genetic traits are inherited. Here we describe the inheritance of an epigenetic modification at the agouti locus in mice. In viable yellow ( A(vy)/a) mice, transcription originating in an intra-cisternal A particle (IAP) retrotransposon inserted upstream of the agouti gene (A) causes ectopic expression of agouti protein, resulting in yellow fur, obesity, diabetes and increased susceptibility to tumours. The pleiotropic effects of ectopic agouti expression are presumably due to effects of the paracrine signal on other tissues. Avy mice display variable expressivity because they are epigenetic mosaics for activity of the retrotransposon: isogenic Avy mice have coats that vary in a continuous spectrum from full yellow, through variegated yellow/agouti, to full agouti (pseudoagouti). The distribution of phenotypes among offspring is related to the phenotype of the dam; when an A(vy) dam has the agouti phenotype, her offspring are more likely to be agouti. We demonstrate here that this maternal epigenetic effect is not the result of a maternally contributed environment. Rather, our data show that it results from incomplete erasure of an epigenetic modification when a silenced Avy allele is passed through the female germ line, with consequent inheritance of the epigenetic modification. Because retrotransposons are abundant in mammalian genomes, this type of inheritance may be common.
Epigenetic marking systems confer stability of gene expression during mammalian development. Genome-wide epigenetic reprogramming occurs at stages when developmental potency of cells changes. At fertilization, the paternal genome exchanges protamines for histones, undergoes DNA demethylation, and acquires histone modifications, whereas the maternal genome appears epigenetically more static. During preimplantation development, there is passive DNA demethylation and further reorganization of histone modifications. In blastocysts, embryonic and extraembryonic lineages first show different epigenetic marks. This epigenetic reprogramming is likely to be needed for totipotency, correct initiation of embryonic gene expression, and early lineage development in the embryo. Comparative work demonstrates reprogramming in all mammalian species analysed, but the extent and timing varies, consistent with notable differences between species during preimplantation development. Parental imprinting marks originate in sperm and oocytes and are generally protected from this genome-wide reprogramming. Early primordial germ cells possess imprinting marks similar to those of somatic cells. However, rapid DNA demethylation after midgestation erases these parental imprints, in preparation for sex-specific de novo methylation during gametogenesis. Aberrant reprogramming of somatic epigenetic marks after somatic cell nuclear transfer leads to epigenetic defects in cloned embryos and stem cells. Links between epigenetic marking systems appear to be developmentally regulated contributing to plasticity. A number of activities that confer epigenetic marks are firmly established, while for those that remove marks, particularly methylation, some interesting candidates have emerged recently which need thorough testing in vivo. A mechanistic understanding of reprogramming will be crucial for medical applications of stem cell technology.
Phenotypic variation that cannot be explained by genetic or environmental heterogeneity has intrigued geneticists for decades. The molecular basis of this phenomenon, however, is largely a mystery. Axin-fused (Axin Fu ), first identified in 1937, is a classic example of a mammalian allele displaying extremely variable expression states. Here we demonstrate that the presence or absence of its characteristic phenotype, a kinked tail, correlates with differential DNA methylation at a retrotransposon within Axin Fu and identify mutant transcripts arising adjacent to the retrotransposon LTR that are likely to be causative of the phenotype. Furthermore, the epigenetic state at Axin Fu can be inherited transgenerationally after both maternal and paternal transmission. This is in contrast to epigenetic inheritance at the murine agouti-viable yellow (A vy ) allele, which occurs through the female only. Unlike the egg, the sperm contributes very little (if any) cytoplasm to the zygote, and therefore paternal inheritance at Axin Fu argues against the possibility that the effects are due to cytoplasmic or metabolic influences. Consistent with the idea of transgenerational inheritance of epigenetic marks, we find that the methylation state of Axin Fu in mature sperm reflects the methylation state of the allele in the somatic tissue of the animal, suggesting that it does not undergo epigenetic reprogramming during gametogenesis. Finally, we show that epigenetic inheritance is influenced by strain background. These findings enable us to propose a model for transgenerational epigenetic inheritance in mammals.I t is generally assumed that a phenotype is determined by the interaction of a specific genotype and a specific environment, but there are a number of examples where variable expressivity and incomplete penetrance cannot be explained by genetic or environmental heterogeneity. One of the earliest documented examples is the axin-fused (Axin Fu ) allele, first identified in 1937 (1). Axin regulates embryonic axis formation in vertebrates by inhibiting the Wnt signaling pathway (2). Axin Fu is a dominant gain-of-function allele that has a 5.1-kb intracisternal-A particle (IAP) retrotransposon (subtype I⌬1) inserted in an antisense orientation (relative to the axin locus) in intron 6 (3). The characteristic Axin Fu phenotype is kinks in the tail (Fig. 1A) caused by axial duplications during embryogenesis (1, 2). The phenotype is variably expressed among Axin Fu individuals, and in some mice the tails appear completely normal; i.e., the mutant phenotype is silent.The variable expressivity of Axin Fu is reminiscent of that observed for the A iapy , A hvy , and A vy alleles of the agouti locus, all of which contain IAP (subtype I⌬1) insertions upstream of the agouti gene (4-6). The coats of isogenic mice carrying these alleles vary from wild-type agouti to completely yellow, with a spectrum of intermediate mottled coats (4-7). The variable expressivity correlates with differential DNA methylation at a cryptic promoter within the l...
DNA deaminases of the Aid/Apobec family convert cytosine into uracil and play key roles in acquired and innate immunity. The epigenetic modification by methylation of cytosine in CpG dinucleotides is also mutagenic, but this is thought to occur by spontaneous deamination. Here we show that Aid and Apobec1 are 5-methylcytosine deaminases resulting in a thymine base opposite a guanine. Their action can thus lead to C 3 T transition mutations in methylated DNA, or in conjunction with repair of the T:G mismatch, to demethylation. The Aid and Apobec1 genes are located in a cluster of pluripotency genes including Nanog and Stella and are co-expressed with these genes in oocytes, embryonic germ cells, and embryonic stem cells. These results suggest that Aid and perhaps some of its family members may have roles in epigenetic reprogramming and cell plasticity. Transition in CpG dinucleotides is the most frequent mutation in human genetic diseases, and sequence context analysis of CpG transitions in the APC tumor suppressor gene suggests that DNA deaminases may play a significant role in tumor etiology.
It is well recognized that there is a surprising degree of phenotypic variation among genetically identical individuals, even when the environmental influences, in the strict sense of the word, are identical. Genetic textbooks acknowledge this fact and use different terms, such as ‘intangible variation’ or ‘developmental noise’, to describe it. We believe that this intangible variation results from the stochastic establishment of epigenetic modifications to the DNA nucleotide sequence. These modifications, which may involve cytosine methylation and chromatin remodelling, result in alterations in gene expression which, in turn, affects the phenotype of the organism. Recent evidence, from our work and that of others in mice, suggests that these epigenetic modifications, which in the past were thought to be cleared and reset on passage through the germline, may sometimes be inherited to the next generation. This is termed epigenetic inheritance, and while this process has been well recognized in plants, the recent findings in mice force us to consider the implications of this type of inheritance in mammals. At this stage we do not know how extensive this phenomenon is in humans, but it may well turn out to be the explanation for some diseases which appear to be sporadic or show only weak genetic linkage.
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