Lecture 5 - Cancer epigenetics Flashcards
example of common TSGs
TP53 gene: Li-Fraumeni syndrome, many types of sporadic cancer
NF1 gene: neurofibromatosis type 1, colon carcinoma…
mechanism for LOH in TSG
- dna mutations
- mitogenic recombination
- Gene conversion
- nondisjunction during mitosis
- epigenetic silencing of TSG
genetics vs epigenetics
genetics: changes in dna sequence (due to mutations)
epigenetics: heritable changes in gene expression without
where does DNA methylation take place
- C of CG nucleotides
- in cancer: DNA hypermethylation in TSGs
how does DNA methylation take place
- DNA methylation recruit specific methyl-CpG binding proteins
- this recruits chromatin modifying enzymes to silence mutations
mechanism of DNA methylation that lead to cancer
- loss of DNA cytosine methylation –> genome instability
- focal hyper-methylation at gene promoters causes silencing of TSGs
- methylated CpG sites prone to mutation –> a. hot spots for C to T transitions, b. methylation of some CpG sites can increase binding of some chemical carcinogens to DNA and increase the rate of mutation
describe DNA organisation and structure
- 30nm DNA fiber
- beads on a string
describe structure of nucleosome
- 4 histone core proteins (H2A, H2B, H3, H4)
- each histone core ~ 102-135 amino acids
- share a ‘histone fold’ structural motif
- 3 alpha-helices connected by a loop
- N and C terminal tails (for epigenetic regulation)
- 1.7 turns of DNA wrapped around nucleosome
- disc-shaped histone core
types of histone post-translational modification
- HAT/HDAC - acetylation/deacetylation
- protein kinase/phosphatase - addition/removal of phosphate
- HMT/HDM - methylation/demethylation
- PRMTI, II/demethylases
active histone marks
histone post translational modifications
- facilitate gene transcription
- enriched in open chromatin regions (euchromatin)
repressive histone marks
- repress gene transcription
- enrich in condense chromatin regions (heterochromatin)
which histone mark shows histone modification in human diseases
H3K4 (histone H3 lysine 4) methylation: leukaemia, hepatocellular carcinoma, hep B virus
EZH2: overexpressed in tumors
what is EZH2
- enzyme for H3K27 methylation
How does EZH2 carry out H3K27 methylation
- EZH2 forms catalytic subunit of Polycomb Repressive Complex 2 (PRC2)
- core subunits EED and SUZ12 assemble in complex
- EZH2 methylate lysine 27 of histone H3 –> chromatin become more condensed
EED: embryonic ectoderm development
SUZ12: suppressor of zeste 12
How does EZH2/H3K27me3 lead to ovarian cancer?
how to combat this
Ovarian cancer:
- EZH2 overexpression
- epigen silencing of TSGs/regulatory genes
- more cancer phenotypes
EZH2 inhibitors
How does EZH2/H3K27me3 lead to B cel lymphoma?
- naive B cells get activated –> they are differentiated into antibody-secreting plasma cells or enter the germinal center (GC) reaction
- naive B cells –> GC B-cells (increase in EZH2 - repress genes regulating plasma cell differentiation)
- GC B-cells reach affinity maturation –> EZH2 decreases –> plasma cell differentiation
*EZH2 mutation –> increase in EZH2 –> sustained repression of proliferation checkpoint & differentiation genes –> GC hyperplasia
hyperplasia: increase in # of cells
KMT2s methylate H3K4
where does methylation occur?
KMT2: lysine methyl transferase
- KMT2C, D: distal enhancer
- KMT2F, G: gene promoters
- KMT2A, B: could function at both regulatory regions
oncogenic histone mutation H3K27M in cancer
what type of cancer
- K27 can be methylated/acetylated but M cannot be modified
- repressive mark
Diffuse Intrinsic Potent Glioma (DIPG)
