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Lect 19: Epigenetics (What are Epigenetic drugs & their uses?
All…
Lect 19: Epigenetics
What are Epigenetic drugs & their uses?
- All common fault of non-selective -> so multiple side effects
- HDAC (FDA approved)
- HAT inhibitors
- Not selective
- Bind multiple protein classes
- Bisubstrate inhibitors were 1st discovered to selectively inhibit HATs p300 & re-express tumour suppressor genes
- Protein methyltransferase inhibitors
- Methylation of lysine & arginine ->catalysed by protein methyltransferases (PMTs)
- Toxic in cellular assays at higher conc
- Methylation inhibiting drugs
- 5-Azcacytidine
- Cytidine analog
- Integrates into DNA during replication (rapidly dividing cancer cells ->more susceptible)
- FDA approved but unstable, toxic side effects
- Zebularine
- Cytidine analog
- Induce re-expression of methylation-silenced genes
- X FDA approved, good results in mouse models
- MG98
- Antisense oligonucleotides
- Re-expression of tumour suppressor gene, p16
- Clinical trials -> mixed results
- Histone methylation inhibitors
- Inhibit trimethylation & re-activate developmentally regulated genes
- 3-deazaneplanocin A (DZNep): selectively inhibits trimethylation of lysine 27 on histone H3 and lysine 20 on histone H4 and to reactivate silenced genes in cancer cells
- HDAC inhibitors
- HDACi only affect 2-10% of expressed genes
- Hydroxamic acid inhibitors -> target class 1 and 2 HDACs and have emerged as a promising & potent treatment for cancers
- FDA approved Vorinostat -> progressive, persistent or recurring T-cell lymphoma
- Hyperacetylation of histones & nonhistone proteins inducing apoptosis & sensitising tumours to cell death processes & drugs
- Multiple targets -> side effects: anorexia, diarrhoea
- AD -> associated with HDAC2 overexpression ->-ve impact on memory formation -> associated with decreased expn of several key neuronal genes including BDNF -> target?
-
Epigenetic machinery DNA methylation
- Methyl grp gets into major grp of DNA -> inhibits transcription leading to gene repression
Histone modification
- Within histones -> unstructured tail -> subject of chemical rxn -> phosphorylation, histone acetylation
- Histone acetylation -> relaxes histone and DNA interactions -> favouring transcriptionally active euchromatin and gene transcription
- 1st component -> non-coding DNA -> x junk DNA -> microRNA plays a vital role in gene silencing, gene regulation and involved in every step from transcription to translation
Impt concepts1) DNA is x destiny
- Agouti mice ->possess Agouti gene->predisposes mice to diabetes and cancer -> makes them hungry -> altered mother’s diet->Agouti gene was conserved from mother to offspring but a gene was switched off->dietary manipulation to change gene expn -> shows DNA has pot to be altered
2) Transgenerational inheritance
- Epigenetic signals from environment can be transmitted from gen to gen without altering gene seq
- Rat model of chronic liver disease -> Fibrosis in paternal lane was protective -> stimulated epigenetic changes in sperm -> offspring protected from fibrosis -> PPARgamma was transmitted ->offspring protected ->Observed over 2 generations
- These proved that everything we do can affect our gene expression and that of future gen
Monozygotic twins -> share a common genotype and are genetically identical -> but sig phenotype discordance ->one of the twin having depression due to environmental factors
1) Epigenetics -> disease susceptibility & variable disease progression
2) Conducting meaningful Epigenome (EWAS) challenging -> Epigenetic -> plastic -> display differences between cells within a tissue & are modified by ageing & environment
Bisulfite sequencing -> tools to interrogate epigenome for DNA methylation
If EWAS + GWAS -> unparalleled mechanistic insigts
- Novel therapeutics
- New prognostic tools
Clinical Practice Model
- Diagnosis -> Prognosis -> Treatment
- Epigenetics having an impact
- Non-alcoholic fatty liver disease (NAFLD fibrosis) -> now common prevalent because of obesity -> see inter-patient variability
Genetics Vs Epigenetics
- Average progression of NAFLD fibrosis -> some patients progress faster
- Plasticity of epigenetic markers in response to environmental & genotypic influence may explain inter-patient variability
- Human hepatic PPARgamma differentiated methylated regions ->stratify fibrosis progression -> pot diagnostic tool
- Epigenetic signatures present in human plasma -> blood based biomarker
- Liver biopsies might become less impt in future
Diseases involving epigenetic changes
Cardiovascular
- Process x understood
- Studies shown epigenetic alteration lead to:
- Atherosclerosis
- Atheroprotective oestrogen receptor genes ESR1 and ESR2 hyper methylated -> repressed so x atheroprotective effect
- Coronary heart disease
- Cytosine methylation in insulin-like growth factor 2 (IGF2) gene
- Dysregn of DNA methylation during embryogenesis -> lead to congenital heart disease & ^ed risk of CVD
- Global loss of genomic methylation content has been found in patients with hypertension
Neurological disorders
- Neuronal differentiation
- CpG methylation lost & H3K4 dimethylation gaind
- Once MeCP2 binds DNA at CpG islands -> facilitates chromosome condensation & gene silencing
- Rette Syndrome
- MeCP2 methylation -> X-linked neurological disorder severe mental retardation
- PD
- Global neuronal hypomethylation
- Late onset progressive neurodegen disease
- Sequestration of alpha-synuclein protein into Lewy bodies, key feature of disease also involves sequestration of DNMT1 into cytoplasm
- Huntington’s Disease
- Decrease in H3 & H4 histone acetylation
- Late-onset progressive neurodegen disorder
Metabolic disorders
- T2D
- Transient hyperglycaemia
- Histone methyltransferase, Set7, recruitment
- Changes in histone methylation pattern of NFkB-65 -> Pro-inflammatory gene often associated with diabetic complications
- Obesity
- Methylation of eNOS, SOD1 genes at birth correlate with adiposity level at age 9
- Leptin: an adipose derived hormone that reg hunger & metabolism -> subject of epigenetic control
Cancers
- Mechanism for cancer progression from stem cells to various metastatic stages remains poorly understood
- Silenced tumour suppressor genes
- Breast & ovarian cancer
- Isolated some tumour suppressor genes such as P21,27
- Methylation of upstream regions caused by upreg of DNMT1 in cancer cells
- In almost all cancer cells the expression of DNMT1 high compared to normal tissue
- Sakar et al.
- Unlike genetic mutations associated with cancer
- Epigenetic changes are reversible & hence a good target for epigenetic therapy
Future goals
- Combo of epigenetic drugs with other cytotoxic drugs
- HDAC inhibition sensitised breast & ovarian cancer cell lines to a variety of cytotoxic drugs
- Clinical trials -> promising results
Infectious Pathogens
- Helibacter pylori
- Gastric cancer risk factor
- Hypermethylation of specific CpG islands in gastric mucosa
- Hepatitis B virus
- Human papilloma virus
- Cervical cancers
- HPV E7 reg DNMT1 & also perturbs chromatin remodelling machinery
Conclusion
- Genetics + Epigenetics + Proteomics + entire lifecourse of individual and everything they exposed to -> multidimensional interactome ->det health outcome of individual
- Genetic + Epigenetic influce diff in disease suceptibilty + progression -> EWAS being undertaken -> Epigenetic signatures highly plastic -> display diff in tissue & modified by ageing + environment ->EWAS+ GWAS offer rewards with insights into disease pathology -> unhealthy epigenetic modification may be modified -> offering epigenetic therapies
- However challenges -> sufficient specificity for a given epigenetic modifier to ensure efficacy & prevent clinical toxicity
- Few HDAC inhibitors passed FDA
- GWAS + EWAS -> design lifestyle modification strategies to prevent disease devt in at risk individuals & passing unhealthy epigenetic traits to future gen