Epigenetics and Abnormal Gene Expression Flashcards
Describe the central dogma of information flow
DNA
(undergoes transcription to become)
RNA
(undergoes translation to become)
protein
How can chromosomes be distinguished ?
By size and G-banding
What is higher DNA structure in the form of ?
Chromosomes
What overlays chromosome structure ?
Epigenetic tags
What is epigenetic information ?
An extra layer of contextual information above just the DNA sequence.
What happens to epigenetic features over time ?
They diverge and change
(seen in identical twin study - older twins have more divergent patterns of epigenetics)
Still identical DNA
What does epigenetic gene splicing involve ?
mechanisms
Multiple mechanisms including:
- DNA methylation
- Nucleosome remodelling
- Histone modifications
What is epigenetics ?
Heritable modifications of DNA that do not alter the primary sequence (e.g. me-C at CpG)
What is the result of epigenetics ?
Altered gene expression
Describe DNA methylation
Covalent modification of a methyl group to cytosine at position C5 to make 5-methylcytosine.
Where does DNA methylation occur ?
CpG islands
- regions of genes that control gene expression
What are CpG islands ?
Most genes have GC rich areas of DNA in their promoter regions.
These areas are called CpG islands.
What causes gene silencing ?
Methylation of the C residues within the CpG islands leads to gene slicing.
DNA methylation in yeast and Drosophila
Little or NO detectable DNA methylation
Key feature of DNA methylation
DNA methylation is heritable
Mechanism of action of DNA methylation
Inhibits gene transcription
Prevents the binding of transcription factors to the promoter
AND
Inhibits transcription by converting chromatin from an open to closed formation.
How does DNA methylation inhibit gene transcription ?
Converts chromatin from an open to a closed formation.
Function of Methyl CPG binding proteins
Methyl CPG binding proteins contain a methyl binding domain that specifically recognises methylated CpGs.
What does DNA methylation recruit ?
Recruits other proteins such as histone deacetylases which remove acetyl groups, favouring compact chromatin.
Causes of disease in epigenetics
Defects in DNA methylation machinery
- X linked syndromes with variable phenotypes
Rett Syndrome
Dominant X linked, neurodegenerative disorder
Caused by a mutation in gene encoding MeCP2, which in turn leads to a loss of gene silencing at many loci.
Who does rett syndrome affect ?
Females only
- males do not survive
Prader Willi syndrome signs
PWS
- mental retardation
- obesity
Angelman Syndrome signs
- mental retardation
- ‘happy puppet’ syndrome
- jerky movements + inappropriate laughter
Causes of Angelman syndrome and Prada Willi syndrome
Chromosome 15 abnormality
AS - maternal deficiency
PWS - paternal deficiency
Occurs due to defects in imprinted genes: defective expression in brain tissue
Heterochromatin
Highly condensed in interphase
Transcriptionally inactive (contains few genes)
Replicates late in S phase
Euchromatin
Organised in 30nm fibre during interphase
Transcriptionally active
Replicates early in S phase
Position effect
Spreading of heterochromatin into euchromatic regions causes cell to cell variability in gene expression.
X chromosome inactivation
LIONISATION
Females need to silence one X chromosome.
Mechanism of silencing is initiated by Xist
Why does X chromosome inactivation occur ?
Discrepancy of 1 X-chromosome in males (XY) but 2 X-chromosomes in females (XX)
Mechanism of X chromosome inactivation
X chromosome is inactivated by transcripts that are made from that X chromosome.
Function as RNA. No protein product and RNA remains in the nucleus.
This is followed by DNA methylation.
Feature of X chromosome inactivation
The X chromosome that gets inactivated is eventually inactivated by DNA methylation.
When does X chromosome inactivation occur ?
Early in embryonic development
Around the 64 cell stage embryo
Klinefelter’s syndrome
Male
Genotype (47XXY)
Number of Barr bodies (inactivated X chromosomes) would also be 1
Barr body
Inactivated X chromosome
Genomic imprinting
Silencing (around 200) DNA genes (individual genes) on autosomes.
Imprinted genes only expressed from 1 allele
Dependent on parental origin
Imprinting resets on passage through germline.
Genomic Imprinting - fertilisation
There is a wave of de-methylation in the fertilised egg, but imprinted genes escape this.
During the production of haploid sperm and egg, the patterns of DNA methylation are re-set for imprinted genes
In sperm, imprint is paternal
In eggs, imprint is maternal
Uniparental disomy
Both copies of a chromosome are inherited from the same parent.
Individual is missing the chromosome from one of the parents
Expression altered of imprinted genes on affected chromosome (non-imprinted genes are not affected)
Chromosome 11 - uniparental disomy
Wilm’s tumour
Chromosome 15 - uniparental disomy
PWS
AS
What is angelman syndrome ?
Genetic disorder that affects the nervous system and causes severe physical and intellectual disability.
Caused when the Angelman gene is either absent or malfunctions.
- paternal uniparental disomy
What is Prader Willi syndrome ?
Rare genetic condition that causes a wide range of physical symptoms, learning difficulties and behavioural problems.
Fault on Chr15 leads to a number of problems and is thought to affect the hypothalamus, which produces hormones and regulates growth and appetite.
- maternal uniparental disomy
AS
Maternal deficiency
PWS
Paternal deficiency
Non-disjunction in Meiosis 2
Uniparental isodisomy
Non-disjunction in Meiosis 1
Uniparental Heterodisomy
Diseases associated with genetic imprinting
Beckwith-Wiedemann Syndrome
Wilms’ tumour
Fragile X syndrome
Myotonic dystrophy
PWS
AS
