Transgenerational inheritance of epigenetic states at the murine Axin ^Fu allele occurs after maternal and paternal transmission

Abstract

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...

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“…However, the DNA methylation can be conserved throughout the process of fertilization in some special cases. 13,14 As evidenced by the study of clone animals, a different phenotype can be produced from the genomes having completely the same DNA sequences. The phenotypic difference between cloned animals and donor should have arisen from epigenetic differences.…”

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“…In other cases, a particular modification can be transmitted from either the father or the mother. The apparent nonmendelian transmission of the mouse axin fused epiallele (Axin Fu ) is one example of this process 88 . The Axin Fu allele contains an intronic IAP retroelement insertion that produces a truncated transcript, leading to a kinked tail.…”

“…The silent methylated state is transmitted to offspring in a strain-specific manner. For the 129P4Rr/Rk strain there is a 70% chance of transmitting the modification when present in the mother and a 40% chance when coming from the father 88 . There is no paternal transmission in C57BL/6J crosses 88 .…”

“…For the 129P4Rr/Rk strain there is a 70% chance of transmitting the modification when present in the mother and a 40% chance when coming from the father 88 . There is no paternal transmission in C57BL/6J crosses 88 . Similarly, methylation of other retroviral regulatory elements may undergo variable erasure during primordial germ cell development 89 producing 'compound epigenetic mosaic' individuals 44 .…”