Transgenerational epigenetics. Flashcards
First type of transgenerational epigenetics (least impressive, but most evidence): LG behaviour, ERalpha, MPOA maternal behaviour rats.
Levels of licking and grooming in mothers. Maternal behaviour phenotype is being passed on. Not fixed in the germline (reciprocal cross-foster experiment shows this is behaviourally transmitted). Low LG leads to other molecular changes, increased DNA methylation of ERα (Oestrogen Receptor α), decreased ERα expression, specific nucleus of the hypothalamus (MPOA). Maternal behaviour phenotype is associated in epigenetic change.
- Reciprocal cross experiment shows this is behaviourally transmitted
o Not fixed in germline
o Maternal behaviour phenotype is associated with genetic change.
Germline transmission: In utero effects (most logical of two): Famine in Ethiopia. Opioid systems and dopamine programming (diet), glucocorticoid system programming (stress), SCZ, ADHD, addictive behaviours (diet). What are the implications of the fact that germ cells develop before birth (DMR F1 hypomethilation, 43% F2, pancreas –> insulin secretion.
. Idea, that when an individual is developing in the womb and the mother is exposed to something, e.g. stress/dietary changes. In the F1 generation, there is an epigenetic. Can see commonly, e.g. pregnant individuals who were in Ethiopia during famine, had offspring who were more resistant to famine when they were in utero.
• Lots of evidence for maternal programming of offspring.
o Animal studies
Maternal diet and programming dopamine, opioid systems
Stress and programming offspring glucocorticoid system.
o Human studies
Maternal diet and predisposition to schizophrenia, ADHD, and addictive behaviours.
Maternal stress and programming offspring glucocorticoid system.
• Germline develops before birth. Epigenetic marks could be established on germ cells. Have consequences for maternal grand offspring.
o Maternal diet led to hypomethylation at DMRs in F1 sperm.
o 43% of hypomethylated DMRs survived reprogramming in F2.
o Key expression of key metabolic genes altered in F2 pancreas.
o Altered insulin secretion.
Paternal germline transgeneral changes (less convincing due to turnover). What do epigenetic changes need to be faithfully passed on to offspring in the paternal germline?
- Paternal factors, such as the mRNAs contained in spermatozoa, have been implicated in the regulation of cleavage during embryogenesis
- This idea is more controversial: While eggs are set in utero, sperm are turned over regularly (but semen is not). If a male individual is exposed to stress that has epigenetic effects on sperm, this may last a few weeks but after all sperm is turned over, should have no effects. For paternal germline changes to be faithfully transmitted to offspring, two major phases of epigenetic reprogramming (i.e. extensive demethylation and methylation) have to be escaped, first occurring in the zygote shortly before the implantation of the blastocyst, and the second during embryogenesis.
Maternal separation/unpredictable maternal stress (MSUS), altered behaviour phenotype –> altered gene specific DNA-methylation in F1 sperm –> altered gene expression in F2 HPC –> sncRNA injection.
• Maternal separation/unpredictable maternal stress (MSUS)
o Altered behavioural phenotype in subsequent generations.
o Altered gene specific DNA-methylation in F1 sperm.
o Altered gene expression in F2 HPC.
o Small non-coding (snc) RNA implicated in transmission of trauma. Take these sncRNA and inject traumatised versions in non-traumatised mice.
Altered sncRNA in sperm of F1.
Olfactory imprinting.
o Increased startle response with exposure to paired smell in subsequent generations.
o Altered DNA-methylation with associated olfactory receptor in sperm.
Limitations of conclusions that can be gathered from transgenerational epigenetics effects.
- Lack of phenotypic robustness and consistency: Males affected in F1, but F2 etc.
- Unclear link between molecular changes and phenotype: olfactory methylation in sperm, but no changes in olfactory system.
