“Epigenetic processes are involved in embedding the impact of early-life experience in the genome and mediating between social environments and later behavioral phenotypes. Since these phenotypes are apparent a long time after early experience, changes in gene expression programming must be stable.
Although loss of methylation in a promoter is necessary for expression, it is not sufficient. Demethylation removes a barrier for expression, but expression might be realized at the right time or context when needed factors or signals are present.
DNA methylation anticipates future transcriptional response to triggers. Comparing steady-state expression with DNA methylation does not capture the full meaning and scope of regulatory roles of differential methylation.
A model for epigenetic programming by early life stress:
- Perinatal stress perceived by the brain triggers release of glucocorticoids (GC) from the adrenal in the mother prenatally or the newborn postnatally.
- GC activate nuclear glucocorticoid receptors across the body, which epigenetically program (demethylate) genes that are targets of GR in brain and white blood cells (WBC).
- Demethylation events are insufficient for activation of these genes. A brain specific factor (TF) is required for expression and will activate low expression of the gene in the brain but not in blood.
- During adulthood a stressful event transiently triggers a very high level of expression of the GR regulated gene specifically in the brain.
Review points discussed:
- “Epigenetic marks are laid down and maintained by enzymes that either add or remove epigenetic modifications and are therefore potentially reversible in contrast to genetic changes.
- Response to early life stress and maternal behavior is also not limited to the brain and involves at least the immune system as well.
- The placenta is also impacted by maternal social experience and early life stress.
- Most studies are limited to peripheral tissues such as saliva and white blood cells, and relevance to brain physiology and pathology is uncertain.
- Low absolute differences in methylation seen in most human behavioral EWAS raise questions about their biological significance.
- Although post-mortem studies examine epigenetic programming in physiologically relevant tissues, they represent only a final and single stage that does not capture dynamic evolution of environments and epigenetic programming in living humans.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952743/ “The epigenetics of perinatal stress”
Other reviewers try to ignore times when we were all fetuses and newborns. For example, in the same journal issue was a Boston review of PTSD that didn’t mention anything about earliest times of human lives! Those reviewers speculated around this obvious gap on their way to being paid by NIH.
Why would researchers ignore perinatal stress events that prime humans for later-life PTSD? Stress generally has a greater impact on fetuses and newborns than on infants, and a greater impact on infants than on adults.