epigenetics and personalised medicine Flashcards
1
Q
Epigenetics
A
“heritable changes in phenotype that do not involve changes in genotype’
2
Q
Chromatin structure
A
- DNA wrapped around histone octamer to form nucleosome
- DNA inaccessible
- Heterochromatin condensed during interphase
○ Contains non-actively transcribed genes - Euchromatin is loosely packaged during interphase
Actively transcribed genes
3
Q
Histone modification
A
N-terminal regions of histone can be altered
4
Q
Types of modification (reversible)
A
- Acetylation
- Methylation
- Phosphorylation
- Most modifications are to H3 or H4
They’re can be modified at multiple sites
5
Q
Naming modifications
A
- Typically lysine (K), serine (S), arginine ( R ), tyrosine (Y)
- Named [histone][amino acid][position of AA in tail][type of mod][number of mods]
- E.g. trimethylation of arginine 11 in histone 3 N-terminal region
H3R11me3
6
Q
Complexity
A
- Different modification to the same Amino acid can have different effects (or opposite effects)
- Modification typically act in combination
○ Active genes have combinations of modifications in genetic components
Silent genes typically have uniform modifications
- Modification typically act in combination
7
Q
DNA methylation
A
- Adding methyl group to position c5 of a cytosine
○ Added by DNA methyl transferases
○ methylated to cytosine normally adjacent to guanine base (CpG)
Cpg methylation
8
Q
Cpg island
A
- Cluster of cpg sites in specific regions of the DNA sequence
○ Typically found in promoter and enhancer sequence- Methylation prevents binding of transcription factors
○ Silencing gene transcription - Allows for tissue/cell specific gene silencing
○ Same gene, tissue a, cell type x
§ Enhanced
○ Whereas same gene, tissue b, cell type y
§ Silenced
- Methylation prevents binding of transcription factors
9
Q
Genomic imprinting
A
- Certain genes show expression ONLY in maternal or paternal alleles
- DNA are methylated with parental methylation patterns
- Upon fertilisation most methylation marks are erase
○ Allows for tissue-specific methylation for tissue development - Some genes escape demethylation
These genes remain silenced
10
Q
DNA methylation in cancer
A
- Tumour-suppressor genes and oncogenes
○ If we turn off tumour-suppressor genes or turn on oncogenes, cancer forms
○ Hypermethylated tumour-suppressor genes - turn off
Hypomethylated oncogenes - turn on
11
Q
Non-coding RNA’s (ncRNAs)
A
- RNA that does not encode a protein
- 2 classes
- Short (<30 RNAs)
○ microRNA (miRNA)
○ Short0interfering RNA (siRNA) - Long (<200 RNA)
Long non-coding RNA (lncRNA)
12
Q
miRNA
A
- Single strand loop
- Partial match target genes (3’-UTR)
- 5’ part of loop is passenger strand
- Pri-miRNA processed by drosha
○ Cleaves 5’ & 3’ tail
○ Exported from nucleus - In cytoplasm DICER cleaves loop
- miRNA is protected by RISC and Ago
○ Passenger strand discarded - miRISC (miRNA + RISC) binds to target mRNA(s)
Degenerative
13
Q
siRNA
A
- Encoded exogenous and endogenous
- DsRNA no loop
- No degeneracy
- Dicer processed
- siRNA protected by RISC and Ago
○ Passenger strand discarded - Activated RISC binds to complementary sequence in target mRNA
Can mediated silencing (gene knockdown)
14
Q
lncRNA
A
- ssRNA
- Guide
○ Help recruit proteins to local site - Scaffold
○ Add multiple proteins together to form complex that interacts with DNA - Decoy
Act as decoy to sequester other miRNAs or transcriptional factors, preventing binding to DNA
- Guide
15
Q
Reasons for genetic testing
A
- Likelihood of getting disease
- Choosing the drug for treatment (pharmacogenomics)
○ Avoid side effects
○ The right drug is prescribed
○ The correct dosage and schedule
○ E.g. CYP2D6
§ If an ultrarapid metaboliser
□ Youll need to increase dosage as the body metabolises it too fast
§ Poor metaboliser
□ Need less as it will stay in the system for an extended period
○ Use genomic data to get therapies that suit unique genotype
§ Breast cancer shows HER-2 over expression - use Herceptin to block - Legal
Ancestry
- Choosing the drug for treatment (pharmacogenomics)
