Epigenetics

Epigenetics

Chemical reactions that alter the physical properties of DNA without changing its sequence

Molecular mechanism of epigenetics

DNA Methylation - addition of methyl groups to cytosine on CpG sites.
Hyper methylation tends to turn off or silence genes.

Histone modification - addition of chemical groups (methyl, acetyl) to amino acids in histones (lysines have + charges that attract DNA)
Methylation can either loosen or tighten association with DNA
Acetylation loosens association by neutralizing + charge on lysines.

Noncoding RNAs can interfere.

Heterochromatin v Euchromatin

Heterochromatin is densely packed with little to no transcription.
Euchromatin is loosely packed with active transcription.

Where are CpG islands?

Included in promoter/regulatory regions of genes

Tags passed to daughter cells

During S phase epigenetic tags are copied to daughter DNA strands.
Methyl groups on parental DNA are copied.
DNMT1 (DNA methyltransferase 1) responsible.

DNMT1 and X-inactivation

DNMT1 adds methyl groups all along inactivated X chromosome, effectively shutting it DAUN!

Nutrition and the epigenome

Certain nutrients required to create methyl groups and insert them into our DNA.
Folic acid, B vitamins, and SAM-e (S-Adenosyl methionine), especially important to take during pregnancy.

Agouti mice experiment

Rat mothers fed BPA (known to decrease methylation of genes)
One mother received diet supplemented with nutrients essential for methylation. Other mother received regular diet.
Offspring of supplemented mother turned out brown and low disease risk.
Offspring of normal diet turned out yellow, obese, and prone to disease.
Yellow mice fed methyl-rich diet had pups that were healthy.

Epidemiological studies of epigenetics (Swedish famine)

Swedish records from periods of famine interspersed with plentiful food supply in the 19th century
- grandsons of men exposed to famine during pre adolescence less likely to die of CVD or diabetes.
- grandsons of men who had plentiful food during pre-adolescence more likely to die of CVD or diabetes.

Epidemiological studies of epigenetics (british 2005)

Sons of fathers who started smoking before 11 at increased risk of being overweight

Challenges of proving epigenetic inheritance

Rule out possibility of genetic changes (must sequence genome first)
Epigenetic effect must pass through 4 generations (3 generations exposed to the same contaminant)
Epigenetic changes are transient by nature

Non-genomic pathways of paternal effects

Female rat may notice cues of the mate itself (anxious, full of toxins, etc) and may not put as much prenatal investment because they dont think the offspring will be that great.

Epidemiological studies of epigenetics (rats)

male rats with high fat diets have daughters with abnormal DNA methylation in pancreatic cells.
Male rats with low protein diets have offspring with abnormal expression of cholesterol genes.
Male rats with pre diabetes have offspring with abnormal methylation in sperm cells an increased diabetes risk
Exposure of preggy rats to pesticides caused organ damage in offspring. Male offspring sperm had differences in DNA methylation that persisted 4 generations (controversial study)

Odour fear conditioning in mice

Male mice fear conditioned to a smell, and they measured hypomethylation in their sperm.
Bred with female mates not exposed to conditioning.
They saw the same thing in the F2 generation. F1 and F2 generation more sensitive to that smell.

Methylation reprogramming

In sperm development, DNA methylation marks are added.
At the zygote stage, DNA methylation is removed.
As the embryo develops, new DNA methylation patterns are added.
In developing reproductive cells, methylation removed again. Cycle starts once more.

Genomic imprinting

Imprinted genes - we only inherit one working copy. The other is genetically silenced.
Imprinted genes bypass epigenetic reprogramming. There are around 100 of them.