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L17 - Relevance of Epigeneitcs II Know the common sites of DNA…
L17 - Relevance of Epigeneitcs II
- Know the common sites of DNA methylation and understand the role of DNA methylation in human cells
- Describe and define the enzymes responsible for DNA methylation and the mechanisms involved
- Be able to describe the influence of DNA methylation on chromatin structure and gene expression
- Understand that demethylation occurs through activity of specific enzymes
- Understand the importance of epigenetics to disease
- Understand that inherited defects can influence epigenetic mechanisms*
Epigenetic Mutations
=> Inherited defects that have an effect through epigenetic mechanisms*
=> Disorders of imprinting
Inherited defects that have a effect through epigenetic mechanisms
- Fragile X (silencing of FMR1 gene à loss of protein)
- Rett's Syndrome (MECP2 protein is a transcriptional regulator)
Fragile X Syndrome
- Most common single gene cause of autism (estimated 5% of patients diagnosed with
Autism Spectrum disorder)*
- Causes intellectual disability, behavioural & learning challenges
Phenotypic Features
including long narrow face,
prominent ears
Aetiology
Most common cause = expansion of a CGG triplet repeat region in the 5’UTR of the FMR1 gene (familial mental retardation 1
- >200 repeats = silencing of the gene.
- Repeats result in C methylation and transcription silencing.
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Genotypic Features
- most frequent allele contains 29 CGG repeats in unaffected people
- Unaffected parents and grand parents => "premutation"
- Offspring with fragile X - have 200 to 1300 repeats = “pathogenic mutation”
Rett's Syndrome
Neurological disorder of the brain’s grey matter => deceleration
of the head growth rate (onset 6 – 18 months of age)
Phenotypic Features
- Small hands and feet
- ~505 cannot walk
- ~80% have seizures
- Typically no verbal communication skills
Aetiliogy
- Main cause = mutations in MECP2 gene (methyl-CpG binding protein-2)
- Affected males die in utero or shortly after birth
- Mostly de novo mutation
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Cancer
- Epigenetic mechanisms responsible for silencing tumour suppressor genes or activation of oncogenes
- Detection of which epigenetic factors control this may be useful in diagnosis and monitoring, or as therapeutic target
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Imprinting Disorders
Results from abnormal methylation of key genes in growth and development.
Imprinted regions disorders are transferred through inheritance of epigenetic tagsduring fertilisation
Defects in methylation or centres controlling methylation, e.g.:
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Developmental origins of health and disease
Impact of environmental/diet during fetal development, infancy and childhood on disease risk in adulthood, thought to be mediated by epigenetic mechanisms
