Lecture 7 Flashcards
What is a metastable epiallele?
Give an example
Locus that can be epigenetically modified in a variable and reversible manner. This changes the phenotype of genetically identical cells
E.g. Agouti - Avy - viable yellow
What does the agouti gene encode?
A paracrine signalling molecule that promotes hair follicles to change from black to yellow
What is the typical agouti pattern?
Hairs that have black base, a yellow band and black tip. Due to agouti being expressed only in the middle part of the hair cycle
What causes the viable yellow phenotype in agouti?
An IAP, murine specific retrotransposon with the Avy allele. If the IAP is hypomethylated then it moves the promoter of agouti from its developmental promoter to this ectopic promoter and the yellow phenotype is seen
What is the effect of IAP methylation happening at different stages of development?
5 distinct phenotypes - from agouti yellow to pseudo-agoutti brown, with mottled individuals between them
Why are the agoutti mice more susceptible to diseases such as diabetes, obesity and cancer?
The ectopic agoutti transcription happens in all cells not just the hair follicles
What effect were dietary supplements shown to have on coat colour?
Crossing Avy/a fathers with a/a mothers showed that when the mothers were given supplements during gestation and lactation the offspring shifted towards more of a pseudoagoutti phenotype
What caused the effect of having dietary supplements?
Increase in CpG methylaiton at 7 key CpG sites in Avy transposon. Hence more expression by developmental promoter
Shown by bisulphite sequencing
Is the effect of dietary supplements inheritable?
F2’s of F0 grandmothers given supplements were more pseudoagoutti
Why did taking supplements increase methylation?
More SAM being produced as supplements are providing components of methionine and hence SAM. More SAM available to supply methyl groups so more methylation
How can SAM be recycled?
After donating methyl group become SAH. SAH converted to homocsyteine
A diet high of what isoflavone mimics the effect of dietary supplements?
Genistein
Give an example xenobiotic chemical
What is its effect on agoutti?
BPA
More yellow phenotype - less methylation (especially in sites 4, 5 and 6)
Effect can be lessened by giving supplements
What effect does BPA have on rats?
Low-dose exposure to BPA increases susceptibility to cancer by changing DNA methylation pattern of important signalling genes
Which IAP has been shown to be affected in mice?
Cabp IAP
Decrease in methylation here too
What component of grapes and red wine has been shown to affect yeast?
Resveratol
What effect does resveratol have?
Activates Sir2 in yeast and extends life span
Mimics effects of calorie restriction via activation of SIRT1 in mammals
How was resveratol investigated using mice?
Mice on low calorie, high calorie or high calorie with resveratol diet.
High calorie individuals life span reduced, slightly increased with resveratol but not to same levels as low calorie diet
What effect did diet have on mice’s physical performance?
Low calorie mice become fitter and performed better ad did high calorie and resveratol mice,however, high calorie only mice did not.
What other effects did resveratol have on the mice?
Increased insulin sensitivity, improve liver histology, increased mitochondria number and decreased acetylation of genes known to be targets of SIRT1; with the expression pattern shifted closer to that of the mice on low calorie diet
What component of green tea effects epigenetics?
How?
Polyphenol
Inactivate DNMT1, resulting in hypomethylation and activation of previously hypermethylated genes
What effect did green tea have in human study?
Drinking 6 cups a day hypomethylated genes involved in gastric cancer development.
What effect did starvation of mice grandmother have?
Males were insulin intolerant when both mother and father were from starved parents. But if one parent was from non-starved parent then the offspring had normal insulin sensitivity
What were the methylation state changes between the mice with grandmothers of different diets?
Non
Probable that it is something to do with histone modifications - but not known
What effect does smoking have on epigenetics?
Causes hypomethylation, in particular of AHRR gene, to increase expression
What is AHRRs role?
Metabolism of benzopyrene - a very toxic component of cigarettes
Outline a link between epigenetics and psychiatric diseases
Bdnf gene is had histone methylated under stress, or taking drugs, which causes depression
Anti-depressants, such as HDAC inhibitors, remove this acetylation to allow expression of the Bdnf
How may genes are differentially expressed between workers and queen bees?
over 500
What effect did Dnmt3 knockdown have in the larvae?
Results in queen rather than worker due to less mehtlyation of CpG island, e.g. in dynactin 62
What natural component of beehives mimics Dnmt3 knockdown?
Royal jelly
What happens when a queen dies in some ant colonies?
Worker ant can undergo epigenetic changes to longevity genes, telomerase and Sir proteins to live longer and become egg layers.
What type of worker ants exist in C. floridanus?
Major and minor workers, that re genetically identical but due to social context, nutrition and physical factors have epigenetic changes
What epigenetic changes occur in C. floridanus?
DNA methylation, changes in H3K27ac by CBP. Affecting neuronal regulation and ageing.
How is CBP expression linked to caste?
Higher in workers and leads to increased intelligence
