Epigenetics and cancer – Flashcards
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what is epigenetics?
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chemical changes to how genome is expressed. methylation, acetylation. packing of DNA
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what is the DNA methylation reaction catalysed by?
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DNMT - DNA methyltransferase
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DNA methylation is used for what?
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Chromatin compaction. Gene transcription silencing. Chromosome and genome stability . X-chromosome inactivation
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what is hypomethylation?
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instability of chromosome, activation of transposons
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hypermethylation causes?
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loss of gene expression
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DNMT1
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is for the maintenance of methylation
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DNA methylation is when?
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there is a loss of acetylated histones
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gene expression is the
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balance between acetlyation and deacetylation
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methylation of H3k9 will lead to
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recruitment of a chromodomain reader, followed by histone deacetylation and DNA methylation
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the trithorax family complexes are
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responsible for euchromatin formation and activation of a locus and contain histone acetyltransferase activity
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bivalent chromatin indicates a region of the genome
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with both repressive and permissive epigenetic marks that can be expressed by removal of repressive marks
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A drug that inhibits histone deacetylases will
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retain acetylation and allow recruitment of bromodomain proteins
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a drug that inhibits one specific histone deacetylase will
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target several to several hundred genes
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a driver mutation is
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a mutation that confers a functional advantage
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passenger mutations can be used to
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follow evolution of a population of cells over time and determine the mutagen exposure over a lifetime of an organism
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comparative genomic hybridization can be used to indentify
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copy number variation
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whole genome sequencing can be used to identify
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classical genetic mutations and epimutations
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GWAS can be used to identify
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copy number variation
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a sample of the histone code can be associated with
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transcription activation, transcription repression, DNA replication, condensed chromatin
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what is the acetylation writer?
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histone acetyltransferase
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histone acetyltransferase
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recruit transcriptional co-activators, act in large complexes, recruit RNA polymerase, turn on gene expression
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histone deacetylase
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recruit DNMT and methyl DNA binding proteins. turn off gene expression
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bromodomain
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reads acetylated lysines
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chromodomain
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reads methylated lysines
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H3k4-methyl
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Transcription ON
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H3k27-methyl
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transcription OFF
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two polycomb repressor complexes
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PCR1, PCR2
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what is an epimutation (3)
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a mutation in a histone deacetylase enzyme. abnormal gene expression due to altered chromatin structure. DNA methylation
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heterochromatin remodelling
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to achieve histone modification and DNA methylation, nucleosomes have to be physically moved around (nucleosome spacing -> enzymes to carry out all the heavy lifting)
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what forms heterochromatin
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methylated DNA, methyl DNA binding proteins, histone deacetylases and the HP1 protein (these all silence a gene)
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why is heterochromatin contagious?
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once the HDAC/DNMT/HP1 complex is active, it gets on a roll and just keeps on going
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stopping heterochromatin spread
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chromatin insulators act as a barrier to stop heterochromatin spreading. maintenance of insulators protect an active locus from heterochromatin
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what is genomic imprinting
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expression from one allele of a gene only, using DNA methylation and insulator sequences (unique to mammals and flowering plants)
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what is the purpose of genomic imprinting
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allows dosage control and explains parent of origin effects
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improper imprinting
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having 2 active copies or 2 inactive copies and can lead to severe abnormalities
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what do paternally expressed imprinted genes do?
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enhance growth of the offspring by increasing use of maternal resources
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what do maternally expressed imprinted genes do?
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reduce the use of maternal resources and control the growth of the offspring
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Prader-Willi Syndrome
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Individuals are missing gene activity that normally comes from dad or when there are two maternal copies
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Symptoms of Prader-Willi
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Learning difficulties, short stature and compulsive eating
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Angelman Syndrome
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Individuals are missing gene activity that normally comes from mum or when there are two paternal copies
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Symptoms of Angelman Syndrome
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learning difficulties, speech problems, seizures, jerky movements and an unusually happy disposition
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a method for studying epigenetic modifications is DNA methylation, what is involved?
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bisulfite sequencing, methyl DNA immunoprecipitation (MeDIP)
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a method for studying epigenetic modifications is Histone modification, what is involved?
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chromatin immunoprecipitation (ChIP)
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EZH2
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writer for H3K27
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BMI1
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reader for H3K27
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PCR1
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maintains silence
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PCR2
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initiates the silence, recruits HDAC + DNMT
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How do mutations arise during DNA replication?
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single base substitutions/deletions/insertions, large deletions, amplifications
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How do mutations arise during mitosis?
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translocations
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How to mutations arise via mutagens?
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Cigarette smoke. Radioactivity. Microwaves and radiowaves .UV light .Viruses. Chemicals
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Mutations can change the (4)
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protein-coding sequences, non-coding RNA sequences, regulatory/promoter regions, intron/exon splice sites
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7 steps from normal to malignant cells
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normal epithelium > dysplastic foci > early adenoma > intermediate adenoma > late adenoma > carcinoma > metastasis
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how do mutations increase survival (5)
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insensitive to anti-growth signals. evade apoptosis. limitless replication. self-sufficient for growth signals. tissue invasion and metastasis
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epigenetic mutations are changed by (5)
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traditional mutations in writers, erasers and readers. spread of heterochromatin. loss of imprinting. environmental factors. erosion of DNA methylation over time.
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epigenetic modifications can be reversed in clinical medicine by
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combinations of DNA demethylators and HDAC inhibitors
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what are the two major forms of genomic instability
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large scale chromosomal duplication and/or loss (CIN, aneuploidy) . small scale changes (DNA expansion and contraction)
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BRCA1/2 interacting proteins do what?
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repair DNA damage
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what are the two types of DNA repair in CRC
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familial and sporadic
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an increased rate of somatic mutation
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leads to a loss of function
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oncogenes are
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dominant mutations - one allele involved. "accelerator" genes, promote cell growth, gain of function mutation, activating mutation. over-ride normal allele
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tumour suppressor genes are
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recessive mutations - both alleles involved. "brake" genes, promote cell growth. loss of function needed
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MYC activity for
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cell cycle, protein synthesis, cell adhesion, metabolism.
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indirect MYC
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apoptosis, genome instability, potentially a very efficient oncogene
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Knudson's two-hit hypothesis
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inherited mutation in one allele, no inherited mutation
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anti-oncogenes
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turn off oncogene
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checkpoint genes
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monitor state of cell
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caretake genes
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repair and maintain genome
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p53 activity
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expressed at very low level in unperturbed conditions. cellular stress of DNA damage activate p53. prevents replication of damaged cells
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epigenome is
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pattern of histone modifications
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switching from OFF (compact chromatin, DNA methylation) to ON (open chromatin, histone acetylation)
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erase negative H3k9, h3k27 methylation and write positive h3k4 methylation
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what is a driver
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instability can be random or nonrandom
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familial refers to a
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mutated classical mutation
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sporadic refers to a
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methylated epimutation
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CpG island methylator phenotype (CIMP)
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cancer specific mulitple concordant methylation of gene promoters
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what is chromosomal instability
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large scale chromosomal abnormalities
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what is microsatellite instability
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expansion or contraction of microsatellite repeats
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what leads to microsatellite instability
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DNA polymerase slippage during replication
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the mutator phenotype hypothesis says
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increased mutation rate is required for acquisition of all the mutations found in cancer genomes
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the epigenetic version of the mutator phenotype is
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CIMP
