Developmental Origins of health and disease

  • Created by: Sarah
  • Created on: 24-05-19 10:28
why would genomic imprinting evolve in the first place?
genes are expressed from either materanl or pateranl copy. May be paretnal conflict between the genomes have diff interests. Paternal- pro-growth they enhance embryo growth, maternal- protecting the mother + enabling to grow several embryos
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what is the maternal genome interested in
protecting the mother enabling her to grow deveral embryos with potentially different paternal origin interested in reducing the size so several embryos have a chnace of developing
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what is an example of demographics influencing epigeentics?
dutch famine- during the dutch famine babies conceived in the last 3 motnhs had significant implications for later on in life and increased risk of diseases- stroke, diabetes, CV disease
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what was the increased risk of disease in dutch famine babies associated with?
differential DNA methylation
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what is this response called?
the predictive adaptive response
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what happened to the predictive adaptive response with dutch famine babies to get disease?
it predicted wrong it had set up the body to make the most of food in times of starvation but when they were born there was plentiful food- environmental mismatch
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how is dveelopment very plastic in regards to genotypes?
the same genotypes can result in various phenotypes
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example that development is plastic and the same genotypes can result in different phenotyes?
shire horse (big) and shetland pony (small), same species so can interbreed. Shetland mother with shire male- progeny size shetland. Shire mother with shetland male- shire size progeny
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what did this tell us?
the size of the newborn horse is determined by the size of the mother although the genotypes are identical
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the maternal compoentn is not only about the size or physical features what else does it have an effect on?
behaviour
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what strains of mice did they use to show the maternal component has an effect?
B6 and BALB mice- differ in colour and behaviour
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what did they do in this experiment?
fertilised egg was either implanted into mother of the same breed then offspring allowed to spend time with parent of same breed or diff breed, tested behaviour
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how did they test behaviour?
open field test- measure of anxiety
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how does the open field test measure anxiety?
rodents want to avoid predators so avoid open areas but like to explore new areas conflict allows us to measure anxiety levels
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what kind of things are used in the open field test?
amount of time walking around the outer edge versus the centre
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where does mouse spend more time if its anxious?
peripheral edges
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what is this test used to look at?
effect of drugs- anxiolytics + axiogeneics- cause and reduce anxiety
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what do anxiolytics do?
dissolve anxiety- spend more time in the centre
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what do you calculate in the open field test?
the amount of time spent in the centre versus periphery
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which strain of mice is more anxious and will therefore spend more time in the edges?
BALB mice
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what are B6 mice?
more exploratory
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what did they find in this experiment?
if BALB mice were transferred into B6 mice or if the B6 Mice were transferred into BALB mice but then raised by B6 they all had B6 behaviour-
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when did the B6 mice show BALB behaviour?
when it had its embryonic period in the BALB mice and then was raised by BALB mice
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what did this tell us?
behaviour was really affected by what the mother of the mice was but how it was raised and what it learnt in the first PN weeks- despite the genotype, pre+PN periods really affect behaviour P6 mice more nervous
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how is it relevant to humans that the same genotype can result in various phenotypes?
presence of diabetes from 60-71 years old (long time after brith) was correlated with birth weight
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what did they find with these correlations?
more prevalence of old age diabetes correlated with low birth weight and a smaller birth weight correlated with higher systolic pressure in men+women over 60yrs
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what does this mean?
the birth weight can have effects on health many years after birth
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what was shown about the birth weight and the number of glomeruli in the kidney?
the lower the birth weight the less glomeruli in the kidney- tight correlation with birth weight
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why would this low birth weight response may have evolved?
low protein diet of the mother activated the gluccorticoid response
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what is glucocorticoid signalling important in regulating?
apoptosis
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what does low protein diet activate?
low protein diet of the mother activates apoptosis by activating the glucocorticoid response so there's cell death in the developing kidney
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why is it important to activate apoptosis when the mother has a low protein diet and activates GR signalling?
limited amount of nutrition goes to other important tissues like the brain and heart which are more important for survival and a healthy life and to reproduce
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what esle has prenatal environment now been linked to?
a wide range of adult conditions including lung disease, cognitive development abnormalities, anxiety, breast cancer, prostate cancer and leukemia
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what does this lead to the formulation of?
that developmental orgiins of health and disease- both pre and postnatal enviorment influences adult health
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what are the benefits of altering development in response to fetal environment?
predictive adaptive response- early environment clues shift the developmental pathway to modify the phenotype in expecattion of the later environment
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what does a low nutrition during prenatal development suggest?
that there would be limited nutrition postnatally so it prepares the organism to increase its chance of surviving and reproduction in the environment thats predicted in fetal development
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example of predictive adaptive response in pontiac butterflies?
wing colour depends on whteher the pupa or caterpillar were pupating/living during the summer or spring
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ones that pupate during spring have what colour? why?
much darker colour- allows more light to be absorbed to heat faster as temp in spring is much lower so allows them to maintain temp+ survive absorb sunlight to raise temp more rapidly
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where is wing colour made? how is it a PAR?
in the imaginal discs in the pupae during morphogenesis but its manifested in the adults so its a predicitve adaptive response
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what is predictive adaptive response?
the response of the development to nutrients and temp gives an organism survival advantages if this response matches the predictive enviroment
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PAR how it it food with fetal malnutrition?
low nutrition in fetus will set the metabolism to be prepared for an enviroment where the food is scarce so it uses every calorie and downregs organs not absolutely required in life
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how were these predictions mostly true?
nutrition in later life matched the nutrition of mother so it allowed to survive to reporductive age
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why did this prediction now become false after the dutch famine?
changes in general food avaliability in the world- post war therefore individuals more likely to be obese and diabetic and have a higher risk of heart disease. low fetal nutrition but not fuflilled in life lots of food enviromental mismatch
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what is the mechansims of these development of health and disease? why?
these are long term effects- some are manifested 60-70yrs after the fetal period suggests changes in gene expr are maintained over a long time- mech of change is DNA methylation as this allows long term changes in gene expression
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does low protein diet cause changes in DNA methylation of offspring?
it does, 618 genes were found to be differentially methylated in livers of rat offspring from mothers on a low or normal diet
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what is behind how the motehrs diet is affecting DNA methylation?
metabolism = the carbon cycle
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what is the really important element produced from the carbon cycle for DNA methylation?
S-adenosyl methinonine (SAM)
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what is SAM a source of?
methyl groups required for methylation
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what do we know about the carbon cycle?
many components are supplied by the diet
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which components of the carbon cycle are supplied by the diet?
Vitamin B12, B6 and F methionine or choline supplied by diet
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why does the mothers diet affect the fetus diet?
fetus is getting food from the motehr- amount of components of the carbon cycle and the efificacy of it happens in every single is dependent on the diet (mothers)
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what genes are hypomethylated in the protein restricted diet?
ppar alpha
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what is ppar alpha?
a TF - major regulator of lipid metabolism
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what targets does PPAR- alpha have?
AOX (acyl-coA oxidase)
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what is AOX (acyl-coA oxidase) for?
Important component of fatty acid metabolism, also the main source of acetyl groups for histone acetylation- changes might go beyond DNA methylation
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how do you get from low protein diet to AOX (acyl-coA oxidase)?
low protein diet -> PPAR alpha hypomethylated --> more PPAR alpha to work on its downstream AOX target
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if PPAR alpha is hypomethylated what is this link to?
high expression- so there's more PPAR alpha mRNA, as TF more transcription of targets such as AOX
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what's another protein thats hypomethylated in the protein restricted diet?
human glucocorticoid receptor
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what does it mean that the human glucocorticoid rec is hypomethylated in the protein restricted diet?
will be more expression of GR so more glucocorticoid signalling and that affects processes eg more apoptosis of nephrons, GR also main stress response so may link to stress response and anxiety
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what does human GR do?
is a TF involved in regulation of multiple processes including hepatic gluconeogenesis through PEPCK regulation
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what is hepatic gluconeogenesis?
generation of glucose from lactate
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what does a protein restricted diet lead to?
changes in the methylation of lots of genes- changes in multiple metabolic pathways which change expression of many proteins
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what component of the carbon cycle absorbed from the diet has been particularly studied?
folate
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what did they test with folate?
if folate supplementation with a restricted protein diet is able and sufficient to reverse the changes in the methylation that is observed in the progeny of mothers
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what happens to PPR alpha and GR in a protein restricted diet?
hypomethylated
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what happens to levels of methylation of PPR alpha and HGR when they have a protein restircted diet but with folate supplementation?
folate acid supplementation completely reverses the change in methylaion- restores expression levels back to normal, as well as the level of expression of downstream genes
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how did they look at whole genome analysis hange in DNA methylation
looked at the control in the animals who were on a protein restricted diet and those who had folate acid supplementation with a protein restricted diet
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what did they see in the progeny og the mothers raised on the protein restricted diet and control groups?
618 differentially expressed genes
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what happened to this differential expression with folate supplementation?
it reversed the changes but some genes were differentially methylated and expressed following folic acid stimulation
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what did this tell us?
there was a good reversal of differential expression but it wasn't complete
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what genes were shown to be misregulated?
DNA methylases- SNMT1, DNMT3a and DNTb
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what else other than the source of methyl groups is affected?
expression of methytransferases
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what suggested it may go beyond just methylation but might affect histone acetylation too?
histone acetyltransferase 1 had altered expression and methylation if mothers had a protein restricted diet
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so what do we know now from limited maternal nutrition?
limited maternal nutrition -> limited fetal nutrition -> abnormal placenta + uterine flow -> both go through methylation or directly alters glucocorticoud concentration, together with limited nutrition alters dev
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what response does it induce?
developmental plasticity response
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what does the developmental plasticity response affect?
tissues such as the liver by reducing liver metabolism or GR signalling apopotosis of nephrons
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examples of big overall effects of low maternal protein diet?
pancreas reduces insulin secretion, muscles cells- decrease in insulin sensitive tissues, HPA axis- increases cortisol secretion, kidney- apoptosis reduced glomruli and neprhon number, vasculature reduced distensibility, endothelial function
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what hapens to the heart?
reduced myocyte number
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is this lethal?
not lethal but newborn will live and reproduce but will have long term consequences on health in the older age- leads to hyperlipidaemia and obesity when food abundant
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what is low maternal nutrition linked to?
diabetes, hypertension and stroke
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is maternal overnutrition good for fetal development?
no- has long term consequences for health
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what happens with maternal highg fat diet?
maternal high fat diet increases the risk of diabetes and obesity
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what protein is has reduced expression in maternal high fat diet?
SIRT1
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What is an increase in the overall acetylation of histone H3 lysine 14 in maternal high fat diet associated with?
reduced expresion of SIRT1
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what is SIRT1?
a deacetylase
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what does liver specific KO of SIRT1 deacetylase do?
increases the probability of weight gain and hepatic steatosis in response to further high fat and cholesterol diet in the adult life
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what is known about maternal high fat diet in nonhuman primates?
maternal high fat diet induced non alcholic fatty liver disease
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linking these 2 bits of information what is this due to?
high fat maternal diet induces reduced SIRT1 activity
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what was in the news about marmite?
marmite prevents miscarriages and birth defects
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what did the paper to do with marmite show?
supplemetation of nicotinic acid with water to male mutant mice allowed the embryos to sustain embryogenesis
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there are 2 pathways in mammalian cells for NAD synthesis what are they?
1) recquired dietary tryphtophan 2) requires ditary niacin = vitamin B
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what is found in marmite?
vitamin B3 (dietary niacin)
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what were the male mutant nice?
mutants in 2 components of the metabolic pathway which converst tryptophan into NAD- the Kyno and Haoo mutant mice
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what happened if the mothers were null for either of these enzymes and at the same time didn't receive any niacin in their diet?
all embryos died- as they couldn't produce NAD which is essential for life
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what happened if they were supplemented with niacin?
live embryos were present and heterozygous embryos were normal as they could produce their own NAD from tryptophan sufficient amount but homozygous mutliple dev defects
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why is it not all that simple that folic acid supplementation restores most of the defects in DNA methylation caused by the protein restricted diet?
protein rich or deficient diet are both bad with folate is the same- moderately high intake of folic acid also had a -ve impact on mouse embryonic development
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what did they do to show high levels of folic acid has a negative impact on mouse embryonic development
mothers were supplemented 10 times the dose for mice
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what did the 10 times recommended dose of folic acid do to the mice?
associated with embryonic delays, embryonic loss and a higher incidence of ventricular septal defects and changes in the heart walls compared to control diet animals
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what is the maternal genome interested in

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protecting the mother enabling her to grow deveral embryos with potentially different paternal origin interested in reducing the size so several embryos have a chnace of developing

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what is an example of demographics influencing epigeentics?

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what was the increased risk of disease in dutch famine babies associated with?

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what is this response called?

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