Biology 1A03 Theme 3 Module 3,4 applied lecture

Single Transduction Cascade can lead to:

signals are detected by cells

Short term: modify immediate cell processes (metabolism, movement) -includes post translational protein modification

Long term: modification of gene expression and/or developement

DNA compacting stages

1. DNA duplex (2 nm diameter)

2.Nucleosome fiber (10 nm)

3. chromatin fiber (30 nm)

4. coiled chromatin fiber(300 nm)

5. coiled coil (700 nm)

6.metaphase chromatid(1400)

What's a heterochromatin?

genes that are not expressed-it contains highly repetitive sequences of DNA that are genetically inactive and serves as a structural element of the chromosome

Epigenetic mechanisms

Chemical DNA modifications that occur along the genome that change gene activity without altering the DNA sequence

1. modification of histone tails

2. DNA methylation

3.chromatin remodelling

4. packaging of DNA around nucleosomes

epigenomics

the study of epigenetic modifications across an individuals entire genome (studied gene by gene)

genome v epigenome

genome is inherited epigenome can be altered

Signals can act on the epigenome to alter gene expression

Epigenetic processes are essential for

normal development, cell differentiation, and are increasingly being recognized as being involved in human diseases

epigenetic mechanisms are affected by these factors:

1.Development (in utero, childhood)

2. Environmental chemicals

3.drugs/pharmaceuticals

4.aging/diet

folic acid in moms diet

folic acid recommended, it minimizes likelihood that baby will be born with open spinal cord, this is a methyl source, so take methyl in diet

DNA methylation

Methyl group can tag DNA and activate or repress genes

Histone modification

binding epigenetic factors to histone tails alters extent of DNA wrapped around histone and availability of genes in the DNA can be activated

epigenetic health results

cancer, autoimmune disease mental disorder and diabetes

Cancer cells and methylation

cancer cells can have lower levels of methylation (increase expression of genes that promote cell growth and they can have higher levels which can decrease expression of genes needed to keep cell growth in check, repair DNA and initiate cell death

-less methyl= genes on

-more methyl=genes off

Gene regulation in Agouti mice

Agouti gene encodes protein that signals to melanocytes to switch from black to yellow mice, also yellow mice r obese

The epigenome leads to these differences (specifically: CpG methylation

Brown mice

agouti gene off bc of DNA methylation

in genetically identical obese yellow sibling mouse:

the same genes not methylated so theyre yellow, obese and predisposed to cancer and diabetes

Experiment of the yellow female mouse with unmethylated and active agouti gene

with diet supplements rich in methyl groups, offspring was 3/4 brown mice and 1 yellow

diet with no supplements- 3/4 yellow mice and 1 brown healthy mouse

In utero you can change underlying genotype and phenotype

how much methyl given :

more methylated agouti increases brown mouse offspring

Nutrients silence the Agouti gene but do not alter the gene sequence

methyl donors include

folic acid, choline, vitamin b12

identical twins

Division of a single fertilized egg with the same genes, and chromosomes and instructions

Blastocyst collapse

cell mass is split in half

comparing DNA methylation twin experiment

Using mapping of chromosomal regions for DNA methylation: hybridization with normal metaphase chromosome

3 year old twins show similar distribution of DNA methylation (lots of yellow so overlap with green and red)

50 y old twins- show changes in pattern of DNA methylation (show hyper and hypo methylation) and show large differences in histone acetylation- 4x as many differently expressed genes

epigenetic drift

how a persons epigenetics change since they were born due to external factors

Dr. Parminder Raina

First study world-wide to measure the evolution of epigenetic markers in a large cohort (50,000 Canadians!)

Relate epigenetic markers to health-related, social and environmental measures

Microarray-based approaches to measure epigenome of subjects over time

Identify candidate genes that appear to be sensitive to epigenetic alterations with age

Human Epigenome project

Important drive to correlate human epigenome with disease

Multinational project with the aim to identify, catalog and interpret genome-wide DNA methylation patterns of all human genes in all major tissues

If successful, can advance field of pharmacogenetics by allowing researchers to develop drugs capable of directly changing the way genes are expressed (epigenomic changes are heritable in somatic cells, but drug treatments could reverse them)