Transgenerational epigenetic inheritance
Transgenerational epigenetic inheritance is the proposed transmission of epigenetic markers and modifications from one generation to multiple subsequent generations without altering the primary structure of DNA. Thus, the regulation of genes via epigenetic mechanisms can be heritable; the amount of transcripts and proteins produced can be altered by inherited epigenetic changes. In order for epigenetic marks to be heritable, however, they must occur in the gametes in animals, but since plants lack a definitive germline and can propagate, epigenetic marks in any tissue can be heritable.
The inheritance of epigenetic marks in the immediate generation is referred to as intergenerational inheritance. In male mice, the epigenetic signal is maintained through the F1 generation. In female mice, the epigenetic signal is maintained through the F2 generation as a result of the exposure of the germline in the womb. Many epigenetic signals are lost beyond the F2/F3 generation and are no longer inherited, because the subsequent generations were not exposed to the same environment as the parental generations. The signals that are maintained beyond the F2/F3 generation are referred to as transgenerational epigenetic inheritance, because initial environmental stimuli resulted in inheritance of epigenetic modifications. There are several mechanisms of TEI that have shown to affect germline reprogramming, such as transgenerational increases in susceptibility to diseases, mutations, and stress inheritance. During germline reprogramming and early embryogenesis in mice, methylation marks are removed to allow for development to commence, but the methylation mark is converted into hydroxymethyl-cytosine so that it is recognized and methylated once that area of the genome is no longer being used, which serves as a memory for that TEI mark. Therefore, under lab conditions, inherited methyl marks are removed and restored to ensure TEI still occurs. However, observing TEI in wild populations is still in its infancy, as laboratory studies allow for more tractable systems.
Environmental factors can induce the epigenetic marks for some epigenetically influenced traits. These can include, but are not limited to, changes in temperature, resources availability, exposure to pollutants, chemicals, and endocrine disruptors. The dosage and exposure levels can affect the extent of the environmental factors' influence over the epigenome and its effect on later generations. The epigenetic marks can result in a wide range of effects, including minor phenotypic changes to complex diseases and disorders. The complex cell signaling pathways of multicellular organisms such as plants and humans can make understanding the mechanisms of this inherited process very difficult.
Epigenetic categories
There are mechanisms by which environmental exposures induce epigenetic changes by affecting regulation and gene expression. Four general categories of epigenetic modification are known.- self-sustaining metabolic loops, in which an mRNA or protein product of a gene stimulates transcription of the gene; e.g. Wor1 gene in Candida albicans;
- Structural templating: structures are replicated using a template or scaffold structure of the parent. This can include, but is not limited to, the orientation and architecture of cytoskeletal structures, cilia and flagella. Ciliates provide a good example of this type of modification. In an experiment Beisson and Sonneborn in 1985, it was demonstrated in Paramecium that if a section of cilia was removed and inverted, then the progeny of that Paramecium would also display the modified cilia structure for several generations. Another example is seen in prions, special proteins that are capable of changing the structure of normal proteins to match their own. The prions use themselves as a template and then edit the folding of normal proteins to match their own folding pattern. The changes in the protein folding results in an alteration in the normal protein's function. This transmission of programming can also alter the chromatin and histone of the DNA and can be passed through the cytosol from parent to offspring during meiosis.
- Histone modifications in which the structure of chromatin and its transcriptional state is regulated. DNA is wrapped into a DNA–protein complex called chromatin in the nucleus of eukaryotic cells. Chromatin consists of DNA and nucleosomes that comes together to form a histone octamer. The N- and C- terminal of the histone proteins are post-translationally modified by the removal or addition of acetyl, phosphate, methyl, ubiquitin, and ubiquitin-like modifier groups. Histone modifications can be transgenerational epigenetic signals. For example, histone H3K4 trimethylation and a network of lipid metabolic genes interact to increase the transcription response to TEI obesogenic effects. TEI can also be observed in Drosophila embryos through the exposure of heat stress over generations. The induced heat stress resulted in the phosphorylation of ATF-2 which is required for heterochromatin assembly. This epigenetic event was maintained over multiple generations, but over time dATF-2 returned back to its normal state.
- Non-coding and coding RNAs in which various classes of RNA is implicated in TEI through maternal stores of mRNA, translation of mRNA, and small RNA strands interfering with transcription via RNA interference pathways. There has been an increase in studies reporting noncoding RNA contributions to TEI. For example, altered miRNA in early trauma mice. Early trauma mice with unpredictable maternal separation and maternal stress were used as a model to identify the effects of altered miRNA in sperm. In MSUS mice, behavior responses were affected, insulin levels, and blood glucose levels were decreased. Notably, these effects were more severe across the F2 and F3 generation. The expression of miRNA in MSUS mice was down regulated in the brain, serum, and sperm of the F1 generation. However, the miRNA was not altered in the sperm of the F2 generation, and the miRNAs were normal in the F3 generation. This provides supportive evidence that the initial alterations in miRNAs in sperm are transferred to epigenetic marks to maintain transmission. In C.elegans, starvation is induced in which survival is dependent on the mechanisms of the RNAi pathway, repression of microRNAs, and regulation of small RNAs. Thus, memorization of dietary history is inherited across generations.
Inheritance of epigenetic marks
Removal vs. retention
In sexually reproducing organisms, much of the epigenetic modification within cells is reset during meiosis, though some epigenetic responses have been shown to be conserved. Differential inheritance of epigenetic marks due to underlying maternal or paternal biases in removal or retention mechanisms may lead to the assignment of epigenetic causation to some parent of origin effects in animals and plants.Reprogramming
In mammals, epigenetic marks are erased during two phases of the life cycle. Firstly just after fertilization and secondly, in the developing primordial germ cells, the precursors to future gametes. During fertilization the male and female gametes join in different cell cycle states and with different configuration of the genome. The epigenetic marks of the male are rapidly diluted. First, the protamines associated with male DNA are replaced with histones from the female's cytoplasm, most of which are acetylated due to either higher abundance of acetylated histones in the female's cytoplasm or through preferential binding of the male DNA to acetylated histones. Second, male DNA is systematically demethylated in many organisms, possibly through 5-hydroxymethylcytosine. However, some epigenetic marks, particularly maternal DNA methylation, can escape this reprogramming; leading to parental imprinting.In the primordial germ cells there is a more extensive erasure of epigenetic information. However, some rare sites can also evade erasure of DNA methylation. If epigenetic marks evade erasure during both zygotic and PGC reprogramming events, this could enable transgenerational epigenetic inheritance.
Recognition of the importance of epigenetic programming to the establishment and fixation of cell line identity during early embryogenesis has recently stimulated interest in artificial removal of epigenetic programming. Epigenetic manipulations may allow for restoration of totipotency in stem cells or cells more generally, thus generalizing regenerative medicine.