BIOL 3000 Epigenetics

Monozygotic offspring

Identical twins, sharing placenta

Dizygotic offspring

Fraternal twins, being of separate placentas

Genome

The genetic material of an organism

Epigenome

Record of the chemical changes to the DNA and histone proteins of an organism

What is erased during the first days post fertilization?

Epigenetic tags from mom and dad’s chromosomes

Imprinted genes

When epigenetic tags are not erased from mom and dad’s chromosomes during the first days of post fertilization

Role of imprinted genes

Transfer epigenetic information rather than just DNA sequence information to offspring

As the embryo develops,

Cell specialization occurs; each cell type specializes with epigenetic tags. These tags either activate or silence specific genes which lead to further specialization

Age 0, genetic tags in a pair of twins can be affected by what?

Nothing yet

Age 3, genetic tags in a pair of twins can be affected by what?

Environmental factors

Age 12, genetic tags in a pair of twins can be affected by what?

Diet

Age 16, genetic tags in a pair of twins can be affected by what?

Physical activity

Age 21, genetic tags in a pair of twins can be affected by what?

Toxins

Age 40, genetic tags in a pair of twins can be affected by what?

Stress

Age 75, genetic tags in a pair of twins can be affected by what?

The cumulation of environmental factors, diet, physical activity, toxins, and stress

What are very different as each twin reaches full adulthood?

Epigenome patterns

Epigenetic effect of methylation

DNA methylase/DNA methyltransferase is added to cytosine to make 5-methylcytosine

This alters the gene expression without changing the DNA sequence itself

DNA methylation role

Usually inhibits the transcription of eukaryotic genes, especially in the region of the promoter

Many eukaryotic genes contain CpG Islands near their promoter regions

CpG Islands

Sequences of DNA typically 1000-2000 nucleotides long containing lots of CG repeats

Unmethylated

No strands of DNA are methylated

Hemimethylated

One strand is methylated

Fully methylated

Both strands are methylated

How does epigenetic control occur?

DNA methylation and chromatin remodeling: Post-transcriptional modification or methylation of DNA

The gene is “switched on” in DNA methylation and chromatin remodeling when:

The chromatin is active (open) and has unmethylated cytosines and acetylated histones

The gene is “switched off” in DNA methylation and chromatin remodeling when:

The chromatin is silent (condensed) and has methylated cytosines and deacetylated histones

Housekeeping genes

Tend to be constitutively expressed in most cell types

CpG Islands are usually unmethylated

Tissue Specific Genes

Gene expression is regulated by methylation at CpG Islands

Block Transcription Factor Binding

The transcriptional activator bind to the unmethylated DNA, which then inhibits the initiation of transcription.

The methyl groups block the binding of a transcriptional activator to an enhancer element

Induction of heterochromatin (chromatin compacting)

1. Methyl-CpG binding proteins binds to the methylated CpG island

2. This protein then recruits proteins, like histone deacetylase, which converts the chromatin to a closed conformation

Gene silencing

Decreasing acetylation (HDAC) allows gene silencing

Increasing methylation (HMT) allows gene silencing

Example of epigenetics

Calico cats

One of the several genes encoding coat color is located on the X-Chromosome X^B (orange) X^b (black). Orange is dominant to black

Lyonization

The inactivation of one random X chromosome so as not to produce twice the gene product

Barr Body

The supercoiled X chromosome (chromatin condensation)

Epigenetics and nutrition

Food contains nutrients like Folic acid and B complex vitamins which are methyl donating nutrients; these help regulate gene expression

Summary of Agouti Mice experiment

The Agouti gene is a gene that influences the coat color in mammals.

A healthy brown mouse briefly had the Agouti mRNA during development, then it was silenced for the rest of life (methylated).

An obese yellow mouse made the Agouti mRNA continuously throughout life, a constitutively active Agouti gene. It has yellow fur.

They took the F1 generation of an obese yellow mouse and fed it foods rich in methyl groups during pregnancy. This resulted in mostly brown healthy offspring, while a normal diet of the yellow mouse led to a mostly yellow unhealthy offspring.

Epigenetic memory

Methylation protection extends beyond the F1 offspring into the next generation, as shown in the Agouti mice

Can we change the epigenetic profiles of specific genes?

Cancer cells have lower levels of methylation than healthy cells, which allows the activation of genes promoting cell growth. It initiates checks on cell growth genes and programmed cell death pathways.

Epigenetics and behavior

A decrease in protein synthesis in depressed patients and a decrease in transcription in AD patients, which are both regulated by methylation.

Studied the increased level of methylation in suicide victims, and there was a correlation with an increase in methylated CpG sites in suicidal victims

Also found that epigenetic markers left in victims of child abuse.