Epigenetics in context

remember, nutrition can have an impact on epigenetics

how does the maternal diet during pregnancy affect genetics?

different diet during pregnancy

• nutritional supplementation

• she could be undernourished or overnourished

This therefore has the following effects/changes in…

• DNA methylation

• histone post-translational modifications

Therefore changes the gene expression for several target genes

• such as changes in fat deposition and energy homeostasis in offspring (and future generations)

what is basically happening in epigenetics?

some genes are switched on and some switched off

bases stay the same but the message changes as DNA is modified

there are 3 main mechanisms that occur - which dont happen in isolation (could happen at the same time or after each other)

1. DNA methylation

2. Modification of histones

3. noncoding RNA

so what is DNA methylation?

shutting genes off - nurture can reverse

it is the tagging of specific points in the DNA molecule with a methyl group - this process usually silences genes

stem cell differentiates into its final form - shuts off genes suitable only for other cell types

inherited daughter cells (differentiation) with the silenced gene

• effects are also reversible

• helps creatures change when their surroundings change

changes in a chromosome without alterations in the DNA sequence

on a chemical level, it is the addition of the methyl group at the 5 position of the pyrimidine ring of cytosine, creating 5-methylcytosine (5-mC)

what was the dutch famine

long-term effects of the Dutch hunger winter

7 months - by Nazis

mothers starved in first 3 months

less DNA methylation of the insulin-like growth factor II (IGF2) gene - major gene for foetal growth and development

methylation was normal in people exposed as older foetuses

what is the mechanism of epigenetics

diet/drugs/chemically

• modify dna

• modify histones

adjust their shape

• to make segments of DNA available

methylation typically decreases gene expression cos it silences the gene

modification of histones

(histones are specialised proteins involved in gene regulation)

histones are made when DNA strands are organised and compacted into chromatin/proteinDNA complexes to safeguard the DNA and make it available or not

the chromatin structure can change when histone proteins are chemically modified - by adding or subtracting a methyl group, acetyl group or other chemical tags

histone methylation characteristically tightens up DNA, restricting access to genes

• acetylation unravels DNA, making genes more available for activation

• epigenetic modifications in histone structures occur within the liver as a result of heavy binge drinking

why is modification of histones significant to DNA modification hence epigenetics?

if a histone is now tightened because of methylation, DNA is less accessible for transcription

to fix this, there can be reversible modifications on their N-terminal tails

there are 8 areas on the histone to allow modification:

• acetylation, methylation, phosphorylation, ubiquitylation, sumoylation, ADP ribosylatiom, deimination and proline isomerisation

Histone modification regulates different functions including

• transcription

• DNA replication

• repair

what is directly affected from diet when modifying histones?

the chromatin

chromatin is made of histones and DNA - specifically it is a string of nucleosomes consiting of DNA wrapped around histones

8 histone proteins = nucleosome

histone modification can impact gene expression by altering chromatin structure

e.g. a high fat, low carb diet could open up chromatin and improve mental ability via histone deacetylase inhibitors

what is non coding RNA (ncRNAs)

we found that they regulate gene expression at the transcriptional and post-transcriptional level

90% of a complex genome is transcribed - not into proteins, but into noncoding RNA (so they arent translated into proteins obvs)

nonfunctional DNA is primarily involved instead, particularly in the regulation of gene expression and is transcribed into ncRNAs

non coding RNA determines the sex of offspring; by shutting down the 2nd X chromsome on female

(only 2% of whole genome is translated into protein)

what is the actual definition of epigenetics

change in phenotype not genotype

study of changes in the regulation of gene activity and expression

that are not dependent on gene sequence (cos methylation etc, so not actual sequences of bases)

there can be heritable changes in gene activity and expression (in the progeny of cells or of individuals) BUT not necessarily heritable if the changes are short term (can be reversed) - only if they are stable, long term alterations 

summarise epigenetic processes

dont act independently

DNA (de)methylation

chromatin remodeling

ncRNAs

can fine tune gene expression

summarise the environmental effects on animals

diet and nutrients have direct and indirect effects

interaction of genetic differences and prenatal environment

25% of the epigenetic variation between babies- genetic differences alone

75% of variation = interaction of genetic differences and the prenatal environment

most of the variation between babies isnt due to fixed genetic changes

most of them are actually due to interactions between the babies’ environment in the womb and genetic info passed down from the parents

what happens if nutrition is poor/inappropriate in utero?

you disturb cell proliferation and therefore cause irreversible changes in tissue structure

you alter patterns of epigenetic remodelling → changes in gene expression

leading to changes in physiological function

can cause disease risk later in life

why shoudl we pay attention to metabolic capacity in epigenetics?

every animal and individual has their metabolic capacity/load - when you don’t give the right nutrients/ or give too much food, it can lead to morning sickness or diseases developing later on in life for the baby

prenatal (foetal) and postnatal stages of development

tell me about what typically happens with mummy dogs

owners typically feed them pre and/or post-natal high calorie diet when they dont need to

this leads to animal babies like puppies being born with elevated blood pressure, adiposity (so more fat cells in relation to muscle cells), and insulin resistance (mice)

being overweight in childhood is a good predictor of excess fat mass as an adult

recent data demonstrates a 16-fold increase in the prevalence of the metabolic syndrome in overweight adolescents compared with normal-weight peers

SO…

mothers who are obese maintain elevated concentrations of glucose and NEFA

induces epigenetic changes

possible permanent changes in appetite control, neuroendrocrine function, fuel metabolism and energy partitioning during early development

leads to greater adiposity and risk of obesity in later life

what was the impact of post war dutch famine

undernutrition in utero lead to insulin resistant babies, so they grew up to be more prone to obesity, hypertension, CHD and glucose intolerance and hence died earlier

this is because excess fat cells were deposited rather than distrubuting equally to tissues which need it

what happens if you give a rat low protein diet

total pancreatic weight decreases

pancreatice B cells decrease

impaires glucose homeostasis (cos B cells produce insulin so less of that means glucose isnt well regulated anymore)

what happens if you give a sheep low protein diet

increase in maternal cortisol in late gestation (cos it stressed them out)

increase in insulin resistance post-natally

decrease methylation (less genes switched off) or increase exposure to glucorticoids changes foetal tissue structure

what is the metabolic adaptation to poor nutrition in horses?

pregnant mum doesnt have enough grass to feed on

so her foal is now preprogrammed not to expect a lot of nutrition (born lean)

so as soon as they have food, their body prepares to take as much of that as possible to lay it out at adipose tissue so when they go back to little nutrition period they use the stored fat to burn it off and stay alive

how does insulin resistance arise in starvation?

becomes a means of adaptation - acc a good thing in some way

cos it minimizes energy loss and facilitates energy storage in the form of fat during spring and summer

helps survival during a subsequent winter famine

high insulin resistance diverts more energy to the insulin independent tissues (brain) and less to insulin dependent tissues

cosidered a thrifty gene - allows animal to survive when food is scarce

remember pregnant doestn mean you should overfeed

image shows a metabolically loaded foal (almost 200% requirement of energy) and deficient in some minerals (optimal is 100%)

what do these images show

you need to be careful how you feed the animal

e.g. soaking hay means you depleting/diluting the minerals from the hay so become undernourished

you can be overfed and undernourished

remember, nutrients have direct effects on genes

B vitamins - folate and B12 might be beneficial if high blood levels of homocysteine

increase in antioxidants decrease DNA methylation

micronutrients are just as important as calories

summary

owners are changing the biology of their horses

epigenetic changes due to

• overfed but undernourished

• often excess calories but poor quality protein

• underfed vitamins and minerals

restriction of forage (hay/grass) decreases fermentation in the hind gut

• redues B vitamin production

• restricted grazing decreases antioxidant intake (fresh grass high in Vit E, flavonoids and phenols)