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Epigenetics - Coggle Diagram

- - - - Reduced gene expression
    - - Increased gene expression
  - - - Switches off important regulators of cell cycle
      - DNMT inhibitors are therapeutic
        
        Myelodysplastic syndrome (blood cancer)
        
        Decitibine is an inhibitor used to treat myelodysplastic
        
        Nucleoside analogue inhibitors
        
        nonnucleoside analogue inhibitors
        
        5-azacytidine
        
        Inhibits DNMTs
        
        Hydralazine
        
        Hypertension drug found to have DNA demethylating abilities
        
        Repurposed
      - Tumour suppressor genes are turned off e.g. p53
        
        Cell cycle progression continues and mutations fall through monitoring system
        
        Chance of tumour occurring increases
    - - Proliferative genes over expressed
    - - Diverse phenotyping across the tumours because different mutations in the DNMTs at different places
      - Spatial transcriptomics
  - - - Only tells you if the DNA is methylated
      - Hard to quantitate
      - Abs are expensive
      - Can say DNA is more or less methylated compared to a standard
    - - Gold standard
      - Can see methylation at specific loci
      - Relies on conversion of cytosine to uracil
        
        5-methylcytosine is not affected by conversion
      - Measured by PCR
      - High resolution
      - 3-step process
        
        Denaturation
        
        Conversion
        
        Desulphonation
- - - - processed by DROSHA to pre-miRNA
- - - - Lysine and Arginine rich tails on histones.
        
        +ve charge amino acids interact with -ve charge DNA
      - Nucleosomes form chromatin fibre
    - - Coil + fold DNA into higher levels of compaction
    - - Octamer of core histones
        
        2 molecules of H2A, H2B, H3 and H4
        
        ~183bp of DNA wrapped round each core
        
        Histone H1 sits on top of nucleosome and keeps DNA in place
        
        Binds to linker DNA (~20-80nt)
    - - 10-100kb loops anchored to a chromosome scaffold
      - Non-histone proteins
        
        Lamins
        
        Topoisomerase II
        
        Enzymes catalyse the unknotting from the scaffold
        
        So that regions of genome are accessible to TFs
        
        Manage topological space that DNA occupies in nucleus
        
        Components of centromeres + telomeres
    - - Heterochromatin
        
        Inactive
      - Euchromatin
        
        Active
    - - Chromatin condenses into chromosomes
      - M-phase
        
        2 daughter molecules fold into 2 sister chromatids held at centromere
  - - - Acetylation
      - Ubiquitylation
      - Sumoylation
      - Methylation
      - Can be activating or suppressing
    - - Phosphorylation
    - - Methylated
    - - Acetylated
      - Methylated
      - Ubiquitanted
    - - Phosphorylated
    - - Histone acetyl transferases (HATs)
        
        Addition of acetyl groups onto histone tails
        
        Can have specific or multiple targets with resepect to histones they modify
        
        P300/CB
        
        Most studied HAT
        
        Acetyl-CoA
        
        Zinc finger binding domain
        
        Acetylates non-histones substrates too
        
        Mice knockout studies show embryonic lethal
        
        necessary for life
        
        Mutations can be acquired
        
        Assoc. with development of B lymphomas
        
        Rubenstein-Taybi syndrome assoc. with mutations in P300/CBP gene
        
        broad thumbs and toes
        
        Inherited
        
        Small height and head
        
        Mental disability
        
        Growth/development defects
        
        Structure
        
        5 protein interacting domains
        
        HAT domain
        
        Bromodomain
        
        Increases gene expression
        
        Relaxes chromatin structure at gene promoter through HAT intrinsic activity
        
        Recruit basal txn machinery and RNA pol II to promoter
        
        Act as adapter molecules
        
        70% p300 binding occurs in open chromatin regions by assoc. of DNase I hypersensitive sites
        
        Exposed regions of DNA sensitive to cleavage by DNase I enzyme
        
        Southern blotting
        
        DNase I digest
        
        1 more item...
        
        Mapping DNase 1 hypersensitivity sites
        
        1 more item...
      - Histone deacetylation
        
        HDACs
        
        Assoc. with gene repression
        
        Multiple classes of HDACs
        
        Class I
        
        1-3 and 8
        
        Control acetylation state of lysine side chains in histone tails
        
        Act as catalytic subunit of several large protein complex with cognate co-repressors
        
        repress gene activity
        
        suggest activity of complexes is regulated by inositol phosphates
        
        Complexes regulated by inositol phosphates
        
        Subclass Sirtuins
        
        Deacylase activity
        
        Deacetylase
        
        Desuccinylase
        
        Demalonylase
        
        Demyrisoylase
        
        Depalmitoylase
        
        NAD+ HDACs
        
        HDAC levels elevated in many cancers and fibrotic diseases
        
        Gene expression reduced
        
        HDAC inhibitors
        
        Aliphatic fatty acids
        
        Valproic acid
        
        Anti-epileptic drug
        
        Targets HDAC I and Iia
        
        High selectivioty for HDAC
        
        In trials for squamous cell carcinoma
        
        Also thought to upregulate apoptosis
        
        Hydroxamate
        
        Benzamides
        
        Cyclic peptides
        
        Mercaptoketone
      - Dynamic
        
        Balance between HATs and HDACs determines overall acetylation status and gene expression
  - - - Addition of ubiquitin protein attaches to substrate protein
        
        Targets Ub-tagged protein for degradation by proteasome
      - Ubiquitin
        
        Small (8.6kDa) regulatory protein
        
        Most eukaryotic tissues
      - General mechanism for protein degradation in any cell
        
        Needed for protein turnover
      - 3 key enzymes
        
        E1, E2, E3
        
        Dependent on ATP
    - - 2A and 2B can be modified
      - H2A
        
        ubiquitinated by Polycomb recessive complex (PRC) 1
        
        Transcriptional repression
        
        deubiquitinated by enzyme BAP1
  - - - Specific targets and enzymes
    - - Well studied histone lysine methyltransferase
      - Member of SET domain family of lysine MTs
        
        SET domain; MT activity
      - Catalyses tri-methylation on H3 at lysine 27
        
        Mono and di methylation too
        
        Assoc. with transcriptional reg. of haematopoiesis
      - Facilitates heterochromatin formation
        
        Silencing gene function
      - Part of PRC2
      - Transfers methyl groups from cofactor SAM
      - Cancer
        
        Elevated or mutated in many cancers
        
        lymophomas and leukaemias
        
        Especially elevated in blood cancers with mutation at tyrosine 641 in SET domain
        
        Activates regulatory genes
        
        cyclin d1
        
        c-myc
        
        Inhibits tumour suppressor genes
        
        Major drug target
        
        Slow tumour growth
      - Mutations assoc. with Weaver syndrome
        
        Rare autosomal dominant genetic disorder assoc. with rapid growth
      - Can cause neurodegenerative symptom in ataxia telangiectasia
        
        Immune system impairment
        
        Increased risk of cancer