Lecture 18 - Epigenetics and Disease Flashcards
What is the difference between epigenetics and epigenomics?
- Epigenetics = Heritable changes in gene expression and cellular phenotype that are independent of changes in the underlying DNA sequence
- Epigenomics = The study of the complete set of epigenetic modifications on the genetic material of a cell (genome)
What are the different contribution of epigenetics to ageing and disease?
- Nature
o Many diseases have a clear genetic basis – Down’s, Angelman’s, Fragile X, thalassemia’s
o Inborn errors of metabolism
Maple syrup urine disease
Phenylketonuria
Familial hypercholesterolemia
o Complex genetic traits associated with obesity and type II diabetes
o Genetic predispositions such as in neurodegenerative conditions and cancer
BCRA1 and BCRA2 mutations in cancer - Nurture
o 1/3 of disease is typically attribute to epigenetics and lifestyle factors
o Epigenetic drift: e.g., Identical twins are born with the same epigenome, epigenetic profiles begin to diverge as they age, differences increase as twins live longer and spend more time apart
o Epigenetic marks are removed randomly as people age
o Environmental influences change the pattern of epigenetic marks - Chance
o Stochastic events play a major role in disease
o Particle interaction with biological molecules
o Free radical damage causes genomic instability – underlying cause of disease – oxidative stress causes DNA damage as well which leads to mutations
What is chromatin?
- Organisation of DNA base pairs is facilitated by compaction and condensation into a complex structure known as chromatin
What is nucleosome?
- The fundamental unit of chromatin
- DNA (146 bp) is wrapped around an octameric histone core consisting of two molecules each of H2A, H2B, H3 and H4
- Further compacted into smaller units
What are epigenetic modifications?
- DNA and chromatin methylation
- Protein (histone) acetylation
- Chromatin ubiquitination (targets proteins for degradation)
- Glycosylation (nutrient sensor)
- Phosphorylation (DNA double-strand breaks)
What is an example of an epigenetic modification?
o Example of an epigenetic mechanism in response to DNA damage: Phosphorylation of the histone variant H2A.X upon the induction of DNA-double strand breaks
What is DNA methylation?
- An addition of a methyl group onto DNA – usually on a cytosine site
- CpG islands: genomic DNA may be methylated at the 5th position of cytosine, typically in the sequence of CpG
- DNA methyltransferase catalyses the addition of CH3 (methyl) from the donor onto the DNA
- CpG island is a promoter region of a gene
- When the CpG island becomes very heavily methylated it switches OFF
How does DNA methylation cause gene silencing?
- Methyl-binding proteins recognise methyl groups
- Causes a repression complex after many bindings
How is DNA methylation aberrant in cancer?
- Global demethylation – increased transcription
- Focal CpG island hypermethylation – transcriptional repression
- Methylation-associated silencing of tumour suppressor genes one of the predisposing hits in Knudson’s classical two hit model of carcinogenesis = EpiMutation
How can DNMT inhibitors act as anti-cancer agents?
- PTEN/PI3K/Akt pathway physiologically plays a key role in the control of many processes essential for the cellular life
- The tumour suppressor PTEN negatively controls the PI3K/Akt pathway and its epigenetic loss, frequent in cancer cells, leads to the aberrant pathways activation
- DNMT inhibitors restore PTEN expression by epigenetic mechanisms
Describe the Agouti mouse study
Genetically identical mice
Agouti gene: gives the mouse the typical colour
Two groups of mice with different nutrition:
Normal diet + high in methyl donors:
* Methyl donors: Folic acid, vitamin Bs
Normal diet
Both groups of mice fed toxic bisphenylate (found in plastics)
Outcomes:
1. Methyl donor group
* Methylation of Agouti gene
* Despite bisphenylate
→ Thin, healthy mouse, brown coat colour
Normal group
* No methylation
* Bisphenylate brings about toxicity
→ Obese, diabetic mouse, like coat colour
What is histone methylation?
- Histone methyltransferases
- Histone demethylases
Trimethylation of lysine 4 on histone 3 (H3Kme3) is associated with transcriptionally active genes
Trimethylation of lysine 9 on histone 3 (H3K9me3) is associated with inactive genes
What is histone acetylation ?
- Histone acetyltransferases (HATs)
- Histone deacetylases (HDACs)
Regulated by the opposing actions of (HATs) which add and HDACs which take one off
What are the types of HDACs?
Class III HDACs – sirtuins (metabolism)
* NAD+ dependent HDACs – Class III
* Sirtuins 1-7
Involved in ageing and longevity as it mimics caloric restriction
E.g., resveratrol (red wine); pterostilbene (blueberries)
Class I, II and IV = metal dependent HDAC enzymes (Zinc = cofactor)
* Class I – HDACs
* Class II – IIa HDACs and IIb HDACs
* Class IV – HDAC 11
What are the types of cancer therapies based on altering the histone acetylation status of cells?
- Prototypical HDAC inhibitor Trichostain A – hydroxamic acid
o SAHA (Vorinostat) which is used clinically for CTCL
o Heavily acetylated histones cause the chromatin to decondense/open up which leads to cell death, apoptosis, killing of the cancer cells this is a result of accumulation of acetylation - Sodium butyrate – small chain fatty acid
o Important pre-biotic and good for microbiome
o Antiepileptic
o Histone deacetylase inhibitors
o Dietary sources
o Products of anaerobic bacterial fermentation in the gut
o Regulate anti-inflammatory immune responses and enhances the epithelial barrier function - Faecal microbiota transplantation (FMT)
o FMT = the administration of minimally manipulated microbial community from stool of a healthy donor into the patient’s intestinal tract
