Epigenetic inheritance of acquired traits through DNA methylation

DNA methylation inheritance, including nuclear DNA methylation and mitochondrial DNA methylation, is a new and controversial issue since the mechanisms are still under heated debate. A better understanding of epigenetic inheritance mechanisms can lead to improvements in genetic evaluation. Exploring DNA methylation inheritance mechanisms could help us draw a better blueprint of how phenotypes can be shaped and provide us with a deeper understanding of evolutionary biology. The DNA sequence can pass inheritable information to offspring by its precise replication during cell division. In mammals, DNA methylation mainly occurs in 5′-Cytosine-phosphate-Guanine-3′ (CpG) by adding a methyl group to the fifth carbon of the Cytosine (5mC). This mark is replicated at each cell division by the action of the catalytic enzyme named DNA methyltransferase 1 (DNMT1). The earliest research regarding DNA methylation inheritance was documented in plants where DNA methylation was correlated to floral symmetry in Linaria vulgaris, proving that the Linaria Cycloidea (Lcyc) gene methylation mutation could be inherited for several generations (Cubas et al., 1999). When talking about DNA methylation inheritance, it is pivotal to distinguish between intergenerational and transgenerational inheritance. The former mainly indicates F0 to F1 transmission but with one exception: the germline (F2) of a fetus (F1) can respond to environmental factors while in utero. Under this condition, the F0, F1, and the future F2 (germline of the fetus) are all exposed to the altered environment, thereby constituting intergenerational inheritance. Transgenerational inheritance means that the altered epigenetic modification can be inherited even if the successive offspring are not directly exposed to the same environment. This paper summarizes the recent progress of 5mC inheritance research in humans and animals, emphasizing dairy cows. The first section of this review summarizes the potential mechanisms involved in DNA methylation inheritance, while sections two and three discuss paternal and maternal 5mC inheritance. The remaining sections include a description of possible mechanisms of mitochondrial DNA methylation inheritance, and 5mC inheritance in different species. Finally, the challenges and limitations of research in DNA methylation inheritance are presented. Several prerequisites must be met to achieve DNA methylation inheritance between generations. Firstly, DNA methylation should be able to pass from somatic cells to their daughter cells as cells are dividing. Secondly, DNA methylation should be capable of being maintaining from the somatic cells to the germline. Last but not least, DNA methylation should resist the two DNA methylation reprogramming events that happen after fertilization and early gonadogenesis. DNA methylation includes de novo methylation and maintenance methylation. De novo methylation requires DNMT3a, DNMT3b, and DNMT3L to establish methylation on unmodified DNA. In contrast, the maintenance of DNA methylation requires DNMT1, which catalyzes CpG methylation in a copy-paste manner, therefore causing symmetrically methylated CpG dinucleotides in both DNA strands. Although this process is stable, if DNMT1 and UHRF1 (ubiquitin-like with PHD and RING finger domains 1) are at a low level, DNA methylation will be diluted as cells divide (passive demethylation) (Harrison et al., 2016). As for active demethylation, it requires the TET (Ten-eleven translocation) protein family (TET1, TET2, TET3) to oxidize the 5mC to 5hmC,5fC, and finally to 5CaC and therefore restoring the non-methylated cytosine status. Current research points to three potential information carriers that could achieve soma to germline transmission: the small non-coding RNA (sncRNA), the chromatin state (histone modifications), and DNA methylation. Chen et al., (2016) proposed that extracellular vesicles (EV) could potentially transfer sncRNA from somatic cell to the germline as the provided evidence that the concentration of tRNAs-derived small RNA (tsRNA) was higher in epididymis than in testis and epididymosomes can fuse with and transfer tsRNAs into sperm, which indicates that mature sperm could absorb sncRNA via EV transfer (Figure 1). Potential pathways for epigenetic information flow. Environmental factors are possible to stimulate the somatic cell and germ cell response. In the somatic cells, epigenetic changes, including DNA methylation, histone PTM (Post-Translational Modification), and small non-coding RNA, could react accordingly and communicate with each other. Besides, the changed DNA methylation status in somatic cells may transmit to the germline via the intermediate of some substrate such as odors, hormones, cytokines, RNA, or metabolites. Furthermore, the altered small non-coding RNA is possible to be passed onto the germline via extracellular vesicles. Potential pathways for epigenetic information flow. Environmental factors are possible to stimulate the somatic cell and germ cell response. In the somatic cells, epigenetic changes, including DNA methylation, histone PTM (Post-Translational Modification), and small non-coding RNA, could react accordingly and communicate with each other. Besides, the changed DNA methylation status in somatic cells may transmit to the germline via the intermediate of some substrate such as odors, hormones, cytokines, RNA, or metabolites. Furthermore, the altered small non-coding RNA is possible to be passed onto the germline via extracellular vesicles. As for DNA methylation, the molecules that mediate the transmission of methylation status between soma to germline could be mobile RNAs, hormones, odorants, metabolites, transcription factors, and cytokines (Allis et al., 2015; Kazachenka et al., 2018). Cytokines are sensitive to environmental stimuli and can be distributed rapidly to the whole body. Besides, sperm have been reported to express hormone and olfactory receptors (O’Hara & Smith, 201