Lecture about paper: Epigenetic programming by maternal behavior Flashcards
There are natural variations amongst maternal care of rats. What variations are there?
High and low licking and grooming (and arched back nursing)
Note: from now on licking and grooming is LG.
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A normal stress system has a high or low sensitivity for negative feedback.
A normal stress system has a high sensitivity for negative feedback.
Explain the genetic pathway that occurs in a baby mouse that has high LG.
High LG results in a healthy stress system where:
- Serotonin (5-HT) is produced that binds to its receptor (5-HT7).
- downstreams cAMP is activated, which activates PKA.
- PKA phosphorylates effector proteins/activators (e.g. CBP) of transcription factors
- CBP binds and activates the transcription factor NFGIA
- NGFIA is able to bind to the noncoding I7 promotor
- transcription of GR (glucocorticoid receptor)
What is the result of the increased expression of GR as a consequence of high LG?
Low corticosterone levels, low anxiety, high licking or grooming.
Explain the genetic pathway that occurs in a baby mouse that has low LG.
In baby mice with low LG, the noncoding I7 promotor is methylated. This prevents that the transcription factor NGFIA can bind to this promotor and this prevents/reduces the expression of GR.
What is the result of the decreased expression of GR as a consequence of low LG?
High corticosterone levels, high anxiety, low licking and grooming
What is parental or epigenetic imprinting?
Epigenetic changes that are already present in the DNA of the cell’s organism. This causes genes to be expressed in a parent-of-origin-specific manner.
Exon I7 has several areas that can be methylated. But when is methylation only possible?
Methylation is only possible when cytosine is followed by guanine (CpG island)
Two regions of the I7 exon are of interest in this article. The 5’ (site 16) and 3’ (site 17) end of the CpG island, seen in the picture. Are there differences in methylation in rats with low or high LG?
Yes, it is seen that the 5’ end or region/site 16 is highly methylated in rats with low LG and almost not methylated in rats with high LG.
3’ end or region/site 17 is methylated in both high and low LG rats. This would mean that methylation of this region, doesn’t interfere with binding of the transcription factor.
What is seen here?
Methylation is also seen in other (15) CpG regions of the I7 exon, for high and low LG rats. But methylation is highest for the low LG rats.
Why can’t you just conclude based on the fact that you see differences in methylation in the I7 exon, that this is the cause of differences in stress levels of rats?
Beause in between epigenetic changes and behavior, are more steps, like mRNA, proteins etc.
What is done in this study to confirm (or deny) that epigenetic changes are the cause of changes in stress level and are caused by the behavior of the mother?
Cross fostering, where the litter from high LG mothers are placed with low LG mothers. If the methylation is dependent on the behavior of the mother, you would expect that the situation created by a low LG mother is restored by the high LG mother.
Can the conclusion of this study be based on solely cross fostering of litter from high LG mother placed with low LG mother?
No, you need to check for causality because high LG mother rats might not recognize adopted litter, so you need a control where the litter of high LG mother is placed with another high LG mother.
What can you conclude based on this picture, where the effect of cross fostering on methylation patterns is measured?
Based on the graph of region 16/5’ CpG, you can state that methylation is dependent on the mothers behavior.
What’s seen in this picture where they measure methylation patterns during embryonic and pup development?
Note: no cross-fostering is performed here
- E20 = embryonic day 20, P1 = first dat of life out of the womb, P90 = adult
- The region 17/3’CpG is not interesting, region 16/5’CpG is interesting.
- You see that in region 16, there’s no methylation during pregancy (E20). Once they’re born (P1) all of the rats have methylation and on P6 there’s a difference between the two groups of high and low LG pups → probably due to the mother’s behavior.