https://www.bbc.com/future/article/20190326-what-is-epigenetics
https://www.theatlantic.com/health/archive/2018/10/trauma-inherited-generations/573055/
https://psychcentral.com/lib/childhood-abuse-complex-trauma-and-epigenetics/
https://www.sciencedirect.com/science/article/pii/S187711731830053X
https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00808/full
https://www.sciencemag.org/news/2019/07/parents-emotional-trauma-may-change-their-children-s-biology-studies-mice-show-how
http://www.pep-web.org/document.php?id=np.016.0045a&type=hitlist&num=0&query=zone1%2Cparagraphs%7Czone2%2Cparagraphs%7Ctitle%2Cepigenetics%7Cviewperiod%2Cweek%7Csort%2Cyear%2Ca#hit1
https://en.wikipedia.org/wiki/Transgenerational_trauma#Epigenetic_transmission
Epigenetic transmission
Previous research assumed that trauma was only transmitted by the parents' child-rearing behavior. However, it may also be epigenetically transferred. Epigenetics studies how gene expression and cellular activity is influenced by external factors such as environment. A vastly researched event of epigenetics modifying genes within generations is the Dutch Hunger Winter Famine. Those directly experiencing the famine suppressed specific genes and expressed other ones that aided in survival. When the survivors had offspring, their children also had the same genes suppressed and/or expressed. Therefore, one way trauma can be transferred is through epigenetics. Furthermore, when a child is raised in the same environment as their ancestors, it can trigger the reformation of a gene in each generation; this is the most indirect form of epigenetic imprinting. The epigenome may also be passed through the gametes. For this to occur, the epigenome must be present in the germline. The epigenome is also extensively reprogrammed during germ cell differentiation and after fertilization to create totipotent cells, erasing many changes that occur during an individual's lifetime.[39] Therefore, the best candidates for heritable epigenetic marks are located at repeat/transposable sequences or regulatory elements that are resistant to reprogramming.[40] Since epigenetic mechanisms can be affected by the environment, it is difficult to determine the extent to which the environment and direct inheritance influence offsprings' epigenome. Therefore, the most compelling studies are in lab settings with controlled environments.
Non-coding RNA is currently one of the most investigated epigenetic mechanisms in the study of transgenerational trauma. Small ncRNAs guide DNA/ histone methylation and post-transcriptionally regulate mRNA.[41] In C. elegans, starvation-induced stress triggered the expression of small RNAs that cause gene silencing and persist for several generations. These generational effects have been correlated with behavioral phenotypes in some studies. When microRNA (miRNA) from the sperm of these C. elegans was injected into fertilized oocytes, the offspring exhibited similar phenotypes.[40] Although the mechanism of this transmission is complex, one hypothesis is that piwi-interacting RNA (piRNA) and exogenous RNAi are involved in a pathway with secondary small RNAs and chromatin regulatory complexes that results in stable transgenerational inheritance.[42]
DNA methylation is another mechanism studied for transgenerational epigenetic inheritance. 5-methylcytosine (5mC) is the form of methylated DNA linked to gene repression in mammals, and N6-Methyladenosineis linked to promotion of gene activity. Various empirical studies have shown that trauma alters methylation patterns in the offspring of survivors, predominantly at the glucocorticoid receptor (NR3C1) gene.[43] For DNA methylation to be inherited, it has to be stable enough to undergo mitosis and meiosis, and it must escape the aforementioned epigenetic reprogramming. 5mc at repeat sequences and rare regulatory elements are resistant to reprogramming.[40] However, it has been hard to find methylated regions that are stable over multiple generations, and there have been a lot of discrepancies across studies. These discrepancies may be due to method of methylation analysis used or due to variations in the epigenome between individuals.
Recent evidence suggests that histone modifications may also be inherited across generations. Histones tend to be preserved at housekeeping sites and developmentally regulated genes in sperm and are preserved everywhere in oocytes.[40] Although it isn't confirmed, if changes in the histone modification machinery were to cause phenotypic changes, a second epigenetic mechanism may be involved.
