Mediators of maternal intergenerational epigenetic inheritance in mammals

Experimental models and epidemiological data suggest that environmental factors, for example, adverse nutrition prior to conception, can lead to phenotypes in offspring of exposed parents in the absence of continued exposure. As a result these phenotypes have been described as epigentically inherited. The mechanistic basis for such phenomena has not been established in most cases. In this review, we consider possible contributing mechanisms for environmentaly induced epigenetic inheritance, with a focus on maternally transmitted effects and by comparing to paradigms of epigenetic inheritance with a clear mechanistic understanding. Genomic imprinting has provided an important conceptual framework for how the epigenetic states of parental germlines can determine allelic expression in offspring, yet, generally speaking, imprinted genes appear resilient to epigenetic disruption from altered parental environments. Metastable epialleles are environmentally sensitive and variably expressed loci that can impact organism phenotype, but the nature of any epigenetic marker at these loci transferred to offspring is unclear. Studies of examples across these forms of epigenetic inheritance show predominant effects are mediated by oocyte factors involved inreprogramming of the genome post-fertilization, rather than direct effects on gametic DNA methylation, with the exception of genomic imprinting. The potential contribution of additional oocyte chromatin features to the specific liability of phenotypic effector genes and their potential to persist through this reprogramming, however, remains to be investigated.