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Epigenetics - MDS1026

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Christian Scerri

on 8 February 2017

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Transcript of Epigenetics - MDS1026

Epigenetics
From the Greek word “epigenesis” - the influence of genetic processes on development
Definition
Genetic control by factors other than an individual's DNA sequence.
Epigenetic changes can switch genes on or off and determine which proteins are transcribed.
Cellular differentiation - Certain genes switched off (inhibited) others switched on (expressed).
Normal cellular processes
Cellular differentiation - Certain genes switched off (inhibited) others switched on (expressed).
Normal cellular processes

Phenotypical differences between identical twins
Cellular differentiation - Certain genes switched off (inhibited) others switched on (expressed).
Normal cellular processes

Phenotypical differences between identical twins
X-chromosome inactivation in female mammals - otherwise females will have twice the number of X-chromosome gene products as males

chemical addition of a methyl group to DNA.

always occurs where a cytosine nucleotide is next to a guanine nucleotide, linked by a phosphate; this is called a CpG site

DNA Methylation

Post-translation modification of histones influence chromatin arrangement - determines whether associated chromatin is transcribed

Two main ways histones can be modified: acetylation and methylation.


Histone Modifications
methylation occurs by DNA methyltransferases (DNMTs)

modifies a gene's interactions with the machinery within a cell's nucleus that is needed for transcription.

one mechanism for imprinting
Addition of acetyl or methyl group to the amino acid lysine

Acetylation is usually associated with active chromatin.

Histone methylation can be a marker for both active and inactive regions of chromatin.

Type of epigenetic change that is responsible for the inactivated X chromosome of females.


Genes can also be turned off
antisense transcripts,
noncoding RNAs,
RNA interference.

Antisense transcripts
- transcribed from the strand opposite to that of the sense transcript (protein- or non-protein-coding genes)
noncoding RNAs
include micro- (mi)RNA molecules - complementary to one or more messenger RNA (mRNA) molecules, generally in 3' UTRs;
RNA interference
(RNAi) - RNA molecules inhibit gene expression, typically by causing the destruction of specific mRNA molecules.
RNA-Associated Silencing
Epigenetics and Disease: Some Examples
Many cancers are a result of inactivation of a tumour suppressor genes

Suppressor genes can be inactivated by DNA methylation.

Two basic models for how tumour suppressor genes can be methylated:
the stochastic model and
the instructive model
Epigenetics and Cancer
>300 epigenetically modified genes have been detected in cancers.
Epigenetics has revealed useful diagnostic and prognostic biomarkers.
Specific hypermethylation patterns on certain genes are reliable biomarkers for particular types and stages of cancer, e.g. aberrant DNA methylation of the GSTP1 gene (amongst over 40 genes) in prostate cancer is a valuable biomarker for the disease (it is found in all biological fluid and biopsies).
Mitochondrial DNA
Though poor in CpG islands, nevertheless, hypermethylation of mtDNA has been associated with amyotrophic lateral sclerosis where they may contribute to DNA methylation-mediated cell death.
Environmental issues
Can cause epigenetic changes

Results might be seen decades after exposure

Epigenetics changes could be inherited by children

Examples include smoking, dietary factors as obesity, hyperglycemia, inflammation, hypoxia and oxidative stress

Interestingly, social factors e.g. stress, parental neglect, can also play a role.
Epigenetic Changes and Infectious Disease
Chronic inflammation and the direct effects of some infectious agents are responsible for methylation induction.

Examples:
Altered patterns of DNA methylation associated with chronic inflammation accompanyng
Helicobacter pylori
infection of gastric epithelial cells are thought to contribute to gastric cancer risk.

Human papilloma virus, Hepatitis B virus and Epstein-Barr Virus have all been linked to methylation problems leading to cancer
Such a therapy does not target the genes themselves, but the enzymes which regulate how and when these genes are transcribed.!

Several drugs targeting DNA methylation and histone deacetylation (HDAC) enzymes have already been approved and others are in clinical trials.

The balance of nucleosomal histone acetylation is maintained through the opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs).

Inhibitors of HDAC activity (HDACi) induce cell cycle arrest, differentiation or apoptosis in tumour cells, and inhibit tumour growth in a variety of rodent models of cancer.

Epigenetic Therapy
Examples of Environmental Factors - Smoking

29 individual CpGs at 18 unique loci that exhibited a greater than 5% difference in DNA methylation levels between smokers and non-smokers.

Most striking difference - the AHRR locus (associated with lung cancer), which showed a 22% DNA methylation difference.

Individual and ethnic differences in susceptibility to methylation can partially explain difference in risk of smoking.

Additional genes that are affected include genes silenced in esophageal squamous carcinoma
Examples of Environmental Factors
-
Helicobacter Pylori

Bacterium that can survive in the mucosal lining of the stomach

Linked with peptic ulcers but also gastric cancer

Inflammatory process triggered by H.Pylori induces methylation changes in genes of the gastric epithelial cells
Many cancers are a result of inactivation of a tumour suppressor genes

Suppressor genes can be inactivated by DNA methylation.

Two basic models for how tumour suppressor genes can be methylated:
the stochastic model and
the instructive model
Epigenetics and Cancer
DNA methyltransferase
Methylation of Tumour Suppressor Gene (TSG) occurs by chance (environmental)

Presence of oncoprotein and suppressed TSG, favours growth of tumour cells.

One problem is that the methylated sites on tumour suppressor genes are commonly located in close proximity, and it is unclear how this could occur by a random process.
The instructive model, an oncogene starts a series of specific molecular events that culminates in DNA methylation of the tumour suppressor gene

Environment plays a minor role in methylation but would play a major role in oncogene activation
Ethyl Alcohol
or better known as alcoholic drinks
Antagonist to methylation agents e.g folate

Results in demethylation -
switching on
genes

1 alcohol drink per day increase risk by about 7%

Moderation is the key word - one drink a day has health benefits e.g lowers risk of heart disease and hypertension

> 1 drink a day - no benefits
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