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, 2015; Milardi et al., 2018), therefore, the male germline could respond to the hormone, cytokine, and odorant fluctuations in the blood (Yankulov, 2015). Two potential models for DNA methylation generational inheritance were proposed, namely, the “escapee model” and the “reconstruct model” (Figure 2). Potential mechanisms of DNA methylation inheritance across generations. Some regions could escape DNA methylation reprogramming after fertilization and the PGC development process in the escapee model. In the reconstruct model, after reproduction process, DNA methylation may re-establish with the help of some small non-coding RNAs or transcription factors. Potential mechanisms of DNA methylation inheritance across generations. Some regions could escape DNA methylation reprogramming after fertilization and the PGC development process in the escapee model. In the reconstruct model, after reproduction process, DNA methylation may re-establish with the help of some small non-coding RNAs or transcription factors. After fertilization, the paternal genome undergoes rapid active demethylation, while slower passive demethylation happens to the maternal genome. De novo methylation then begins in blastocysts as tissues start to differentiate. Subsequently, a second more complete demethylation occurs during primordial germ cell (PGC) migration to the undifferentiated gonad. However, DNA methylation reprogramming does not eliminate all DNA methylation marks (Irmler et al., 2020), and some regions can resist this process and act as the so-called “escapee” marks (Figure 2). Imprinted genes, for example, expressed only from one of the parental chromosomes, are regulated by methylation of imprinting control regions (ICRs). During the gametogenesis process, a non-erased imprint may lead to lethality or other specific diseases (Buiting et al., 2003). Besides, other regions such as repetitive elements, evolutionary young retrotransposons, and some single copy loci can escape the DNA methylation reprogramming process and, therefore, can be theoretically transmitted to future offspring (Table 1). For example, many loci were reported to act as escapees in humans, as they were at a minimum of 30% methylation level in the PGC development process (Tang et al., 2015). In this well-designed research, approximately 1,400 escapee regions were in repeat-free loci, mainly in promoter, enhancer, gene body, and CpG-island (CGI) regions. The Transforming Acidic Coiled-Coil Containing Protein 2 (TACC2) is an example of an androgen-responsive cell cycle regulator with an escapee region in its promoter. Many of these escapee-associated genes are expressed in the brain, with latent association to nerve and metabolic disorders (Tang et al., 2015). Reported regions and elements that have the escapee character Note. + indicates the regions or elements that had an escapee character had been reported. Reported regions and elements that have the escapee character Note. + indicates the regions or elements that had an escapee character had been reported. Another study in mice showed that 4,730 loci could escape the PGC methylation reprogramming. More than 95% of these loci were repetitive elements, and 233 single copy loci with a methylation level higher than 40% were observed. Interestingly, these escapees were always adjacent to telomeric or intracisternal A particle (IAP) elements (Hackett et al., 2013). The IAP is an endogenous retroviral sequence and constitutes a class of transposable elements that could induce genomic mutations. Regions and elements that can escape the DNA methylation reprogramming process are summarized in Table 1. In 2013, Jablonka proposed that environmentally induced DNA methylation could be partially erased when transmitted to the next generation (Jablonka, 2013). Therefore, even if the observed phenotype may disappear in the F1 generation, the altered phenotype could be observed again in later generations following a minor environmental stimulation. Later, Miska & Ferguson-Smith (2016) proposed that sncRNA, transcription factors, and metabolic loops could regulate this reconstruct process (Figure 2). The reconstruct model was later partly confirmed by Kazachenka et al. (2018), as their study proved that the methylation of the variably methylated IAP transposons could be re-established between generations. These variably methylated IAP transposons are flanked by binding sites for CTCF (CCCTC binding factor), CTCF is known as a transcription factor, which can be considered a modulator of the methylation status. Therefore, the variably methylated IAPs could be inherited by offspring in a reconstructed way with the help of CTCF. The possible interplay between DNA methylation, small non-coding RNA, and histone PTM is summarized in Figure 1. The loss of H3K9 methylation in embryonic stem cells had been reported to cause CpG methylation to decrease in centromeric satellites, indicating that DNA methylation can be directly regulated by histone methylation such as H3K9 methylation (Lehnertz et al., 2003). Meanwhile, DNA methyltransferase (DNMT) and methylation CpG binding domain (MBD) could recruit complexes containing histone deacetylases (HDACs), therefore influencing histone acetylation (Bird, 2002). Thus, histone PTM and DNA methylation could regulate and influence each other. As for sncRNA, they could also modulate DNA methylation and histone modification. Small non-coding RNAs usually function by silencing the target mRNA. This process recruits Argonaute (AGO) or PIWI (P-element Induced Wimpy testis) proteins, which lead to further recruitment of chromatin-modifying enzymes (CMEs) or DNA methyltransferase (DNMT), thereby regulating histone modification and DNA methylation. Only the germline has the potential to carry nongenetic information to the next generations. Many factors were reported to influence paternal DNA methylation inheritance. For example, nutrition has a significant impact on DNA methylation inheritance. In rodents, offspring of male rats fed a high-fat diet harbored specific DNA methylation patterns (Ng et al., 2010) and showed a reduced birth weight and decreased numbers of islet B cells (de Castro Barbosa et al., 2016), besides, after being fed with a high-fat diet, the sperm of the F0 and F1 rats showed similar DNA methylation and microRNA profile changes (de Castro Barbosa et al., 2016). In male mice, abnormal sperm DNA methylation triggered by prediabetes could also be transmitted and increased the risk of diabetes in the following two generations (Wei et al., 2014a). Other environmental triggers such as chemical molecules were also reported to induce paternal DNA methylation inheritance. The exposure of gestating rats to high doses of endocrine disrupters such as insecticides and fungicides resulted in altered sperm DNA methylation in male offspring, lasting at least four generations (Anway et al., 2005). Similarly, the F1 male offspring of mice exposed to endocrine disrupters during pregnancy showed spermatogenic disorders accompanied by methylation alterations. Interestingly, there were no significant effects in female offspring in this study (Anway et al., 2005). Besides, other endocrine disruptors such as bisphenol A had also been reported to alter sperm DNA methylation, causing hypomethylation of Long Interspersed Element-1 (LINE-1)(Miao et al., 2014). Weyrich et al. (2016) demonstrated that exposure of male wild guinea pigs to high temperatures decreased DNA methylation levels in the liver and testis of F0 and F1 (Weyrich et al., 2016). In zebrafish, maternal DNA methylation profiles are only preserved until the 16-cell stage after fertilization, and then they are erased and reprogrammed. At the blastocyst stage, maternal DNA methylation mimics the sperm methylation profile, indicating that the father plays a more significant role in DNA methylation inheritance in zebrafish (Jiang et al., 2013). Imprinted genes, heterochromatin in centromeric-pericentromeric regions, and repeat elements had been reported to escape DNA methylation reprogramming on the maternal side (Ge & Sun, 2019). The most persuasive evidence of maternal DNA methylation inheritance is the Agouti viable yellow (Avy) loci in mice. Although genetically identical, the coat color of the mice may range from entirely brown to yellow, the methylation of transposable elements could explain this quantifiable color transition phenomenon. The mothers of yellow agouti mice tend always to bear offspring of identical coat color, which can be observed through multiple generations (Cropley et al., 2006). In rodents, transposable elements make up approximately 40% of the whole genome, and most transposons are usually methylated to maintain genome integrity. Only 1% of them could be variably methylated, which means that they could respond to external factors and be inherited by future generations (Kazachenka et al., 2018). Another well-documented example is the Axin-fused (AxinFu) mouse model. In this model, IAP methylation regulates the tail kink phenotype within AxinFu, and DNA methylation can be maternally and paternally inherited in this model (Rakyan et al., 2003). The two cases mentioned above are both transposon methylation inheritance. Considering the factors that affect maternal DNA methylation inheritance, nutritional intake (zinc, vitamin B12, folic acid), maternal obesity, and diabetes can all influence DNA methylation in oocytes, indicating a latent maternal intergenerational DNA methylation inheritance. Similarly, chemicals can also alter oocyte DNA methylation. The exposure of female mice to chemicals such as cyclophosphamide (CPM) before conception resulted in methylation alterations in F1 oocytes, which can be further passed on to the F2 generation (Giovanna et al., 2019). The mitochondrion has a unique structure and is maternally inherited, since sperm mitochondria DNA is in the middle piece of the sperm body and will be lost during fertilization. Abnormal mitochondria DNA mutations can be maternally inherited for several generations (Ge & Sun, 2019). its DNA and this can DNA and are no or regions in the mitochondrial genome, and the structure gene and gene in mitochondria is with methylation, which in different including CpG methylation, methylation, and methylation. The enzymes DNMT1, DNMT3a, DNMT3b, and TET2, were in proving the of CpG methylation in this research that 5mC is maternally inherited, in regions. 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