Epigenetics Flashcards
How might an individuals obesity effect their offspring?
Fetal/neo-natal programming of obesity, diabetes and metabolic function through epigenetics
What is epi-genetics?
Refers to the study of heritable changes that affect gene function without altering the DNA sequence so changes that do not pertain to the DNA sequence but are changes to DNA, such as tags, that can be transmitted
* These changes result from external/ environmental factors such as age, nutrition, lifestyle, etc. They participate in the development of several diseases
* These changes are heritable, either in the progeny of cells or of organisms.
* From epi(outside)-genetics
What controls gene expression?
DNA and histone modifications → Can have changes on DNA itself (e.g. methylation on DNA) and can have modifications on histones (e.g. methylated, acetylated, phosphylated) which determines if DNA can be active for transcription or not
* Switch from active to inactive (and viceversa) as a result of epigenetic changes
* DNA can either be closed and not available to transcription OR it can be relaxed
How do epigenetics develop throughout life?
Can occur all throughout life and is dependant on environment. Ageing also induces epigenetic changes
Describe the genome-wide analysis that was done of histone H3 methylation
Studied changes on genes that can be induced by smoking. Those that stopped smoking has some reversible changes and permanent 20 years later.
* demonstrates there may be epigenetic changes with smoking.
* invovled some regions related to cancer.
Describe how analysis of genome can be done
Piece of DNA and looking at the histones and can see what areas are activated versus inhibitory and then this determines gene expression.
* Histones can undergo changes. then measure those modifcation using antibodies (arrows pointing to it) and tag using fluoresent probes to results on the graph
* some changes are permanent and some are temporary
* important for controlling normal biology (e.g. animals with white coat in winter and brown coat in summer are to do with epigenetic changes)
Marked epigenetic differences in T2D islets
Looked at epigenetic changes in islet cells for people with diabetes vs control.
* marked histone modifications. noticed there is a signature that you can recognize (more red on controls vs. T2D)
* Showed less methylation (green) for T2D than control (each row is different gene so can survey individual rows)
Epigenetics regulation of beta-cell mass and function
Islets were exposed to normal condition, high glucose, high lipids and both together and found that a lot of genes were expressed differently
* expsoing islets to glucose found that 8 genes were exposed differently
* lipids had a profound effect and were expressed differently
* lipids and glucose found thousands of altered genes and methylations
* With accumulation of the epigenetic changes, islets will have a tough time secreting ATP
Diabetogenic modifications of the epigenom
All factors that occur on muscle, liver and pancreas may contribute to T2D
* Some we cannot do anything about but lifestyle factors may be modified and will effect methylation of epigenome
Is a short episode of hyperglycemia sufficient to
cause permanent “damage”?
Gave high levels of glucose for a few hours then removed
* epigenetic changes were permanent
* short episode of hyperglycemia was sufficient to makes changes to genetic expression and going back to normal levels did not reverse the changes
* Changes in inflammation (NF-kB)
Epigenetic inheritance of body weight
Parent mice were fed low fat diet, normal diet, and high fat diet then bred together with all the possibilities
* Mice that had at least one parent with high fat diet displayed higher body weight and thus greater susceptibility to insulin resistance and diabetes (width shows number of mice at that particular value)
* differences were bigger when looking at females
Which parent has a great effect on obesity inheritance?
Mothers tend to have more effect since they are providing the utero environment
* driven by epigenetic changes
Offspring characteristics from obese maternal characteristics
- A: offspring of mother will eat moree calories compared to control
- B: body weight increaes because they more (males and females); born at the same weight but as they grow older they have increases in intake and BW
- C: increased fat mass, TG, cholesterol, major increases in insulin, leptin
Cardiovascular effects in offspring of obese mice
higher BP, lower HR, less active, glucose does not go back to normal it is always at a higher level
Insulin resistance effects in offspring of obese mice
- glucose does not go back to normal, always at a higher level
- even with more insulin were not able to bring glucose back to normal values
Adopsity in offspring of obese mice
- white bars: most adipocytes smaller diameter
- offspring (black) had alrger adipocytes indicating increased adipocity
Changes in hypothalamic regions in offspring of obese primates
Maternal overnutrition programs epigenetic changes in the hypothalamic regions of primate offspring
* reduction on POMC mRNA and stimulation of AgRP mRNA meaning animals would be more hungry
* all cytokines were increased which were studied as markers og hypothalamic inflammation
Changes in anxiety in offspring of obese primates
Maternal high fat diet consumption increased anxiety-like behavior, depession and hoarding in primate offspring
* control when exposed to new toys would be interested/ enthusiastic and take onyl second to touch toy but offspring with HFD wouldnt play as much and took them longer to touch the toys
* control animals were not as interested in food and would only get it when they were hungry but the anxious monkeys displayed signs of hoarding and selected foods richer in food even when they werent hungry
How might mothers milk of obese rats effect offspring?
Obesogenic effects from both milk and utero of obese maternal characteristics
* PL = milk fed from obese mother
* MHF = obese mother during utero
How does obesity alter food choices and dietary intake in rats?
Ate more
* increase CHO, fat, sat fat, sucrose, salt, preferred palatable foods
* less protein, less fibre
How has embryo transfer shown the importance of utero programming?
Took lean/ obese mothers and swapped the embryos
* lean to lean = nothing happened
* lean to obese = gained more weight
* obese to lean = remained lean in adulthood
saw differences in NPY, AgRP and less insulin receptor in hypo so less effect of insulin in HC group (?)
Results of gestational diabetes and transfer to offspring
If mother has gestational diabetes, you are at risk of developing it later in life too
* neither diabetic have low chanve of developing diabetes, lower risk for needing insulin of you do have diabetes
* mother has greater risk than father
* both = higher risk and greater chance of needing insulin for glucose control
Summary of the effects of epigenetics in development of obesity/ T2D in offspring
What can help to break the cycle of obesogenic inheritance?
lifestyle choices such as PA and diet
* Exercise induces promoter hypomethylation to alter gene expression
* PA can result in more gene expression which may help to revert the changes that were done from ↑ glucose and ↑ fat
* can target things such as improving mito numbers and taegeting glitosomes
Genetic and epigenetic catalysts in early-lifeprogramming of adult cardiometabolic disorders
Summary of the effect of the maternal diet
Summary slide
