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Epigenetics - Coggle Diagram

- - - - More or less active
  - - - 2 types of chromatin defined based on chromosome staining properties
        
        Euchromatin
        
        Decondensed
        
        Transcriptionally active
        
        Heterochromatin
        
        Condensed
        
        Transcriptionally inactive
      - Nucleosomes
        
        In eukaryotes, chromatins structural subunit is a nucleosome
        
        146bp DNA wrapped around an octamer of basic histone proteins
        
        Each nucleosome core consists of 2 copies of H2A, H2B, H3 + H4 histones
        
        Each octamer consists of
        
        Globular C-terminal domain
        
        Critical to nucleosome formation
        
        Flexible N-terminal tail
        
        Extends from nucleosome core
        
        Crucial role in modulating nucleosome structure + function
  - - - Methyl groups derived from dietary methyl donors
      - Methionine metabolic cycle is central
        
        Part of integrated metabolic pathways known as one carbon metabolism
        
        Methionine converted to S-Adenosyl Methionine (SAM)
        
        Principle methyl donor
        
        S-Adenosylhomocysteine (SAH) is formed
        
        Demethylating product of SAM
        
        SAH hydrolysed to homocysteine
        
        Catabolised
        
        Re-methylated to methionine
      - Modification of DNA base cytosine to 5-methyl-cytosine
        
        At CpG dinucleotide sites
        
        Covalent addition of methyl group to 5' position of cytosine ring
        
        SAM substrate - donates methyl group
        
        Changes base itself but does not alter coding function
        
        3-4% of cytosines are methylated in normal human DNA
        
        Modulates gene expression
      - DNA methyltransferases
        
        Methylation of mammalian genomic DNA catalysed by DNA methyltransferases (DNMTs)
        
        Divided into
        
        de novo (DNMT 3A + 3B)
        
        Methylate cytosines to 5-methylcytosines post-replicatively in un-methylated DNA
        
        Maintenance (DNMT 1)
        
        Attaches a methyl group to hemi-methylated DNA during replication
    - - DNA is negatively charged
        
        Can be more tightly packed when histones are positively charged
        
        Via deacetylation
      - Acetylation by histone acetyl transferase (HAT)
        
        Acetyl-CoA --> CoA
      - Deacetylation by histone deacetylase (HDAC)
        
        H\(_2\)O --> Acetate
    - - KMT-mediated protein methylation
        
        KMT = lysine methyltransferase
      - Lysine residue can receive up to 3 methyl groups
        
        3 possible methylation states
        
        Mono-methyl lysine (me1)
        
        Di-methyl lysine (me2)
        
        Tri-methyl lysine (me3)
  - - - MeCP2 binds methylated DNA + recruits HDAC1 facilitating repression via histone deacetylation
        
        MeCP2 recruits DNMT1 to facilitate methylation of hemimethylated DNA
        
        Conformational change of MeCP2 recruits HDAC1
  - - - Polysumoylation
    - - Polyubiquitination
    - - Dimethylation
        
        Trimethylation
- - - - As cells differentiate they are re-established
    - - Differentiated cells cant be formed into another cell type
  - - - One X chromosome is selected at random in each cell of embryo + permanently switched off
    - - Gene for coat colour encoded on X chromosome
      - Distinctive patched of different coloured fur come from skin cells that have one inactivated X chromosome or the other
      - Random process means no 2 cats are the same
  - - - Genetically identical
      - Developmental divide controlled epigenetically
        
        Differential feeding with royal jelly
        
        Female larva destined to become queen fed large quantities of royal jelly
        
        Triggers cascade of epigenetic events
        
        Changes to DNA methylation
  - - - Role in tumour formation
      - Explain how environmental triggers cause cancer
    - - Molecular modifications to foetal + maternal DNA could make people more susceptible to type 2 diabetes or CVD
    - - Cognitive decline in normal ageing conditions
        
        Alzheimer's
      - Schizophrenia
      - Bipolar
      - Autism
    - - Systemic lupus erythematosus, asthma, insulin resistance in obesity + diabetes thought to have environmental component
  - - - DNMTi + HDACi (inhibitors) have FDA approval/under clinical trials
      - HATi also show great promise
      - Novel therapies e.g. HMTi + HDMi (targeting histone methylation) have been suggested
      - Anti-tumour effects by inhibiting growth or inducing apoptosis
      - Re-sensitisation of cancer cells to chemotherapy by modulating drug response genes/pathways
      - Cytidine analogues - DNA hypomethylation agents
        
        Incorporated into DNA/RNA as methyl group cannot be added to N-5
        
        Bind + inhibit DNA methyltransferases
- - - - Smoking associated with decreased methylation of coagulation factor II receptor-like 3 gene (F2RL3)
        
        Increased expression of protease-activated receptor-4 (PAR4)
        
        Induces platelet aggregation
        
        Possible mechanism for increased CVD risk
  - - - British residents belonging to South Asian, African + African Caribbean race are at heightened risk of suffering type 2 diabetes compared to European descent
        
        Can these be accounted for by genetic differences or other factors?
      - Large no. methylation sites differ between ethnic group
        
        Differences associated with type 2 diabetes?
    - - Methylation score higher in Indian Asian individuals compared with Europeans
      - Potential risk stratification + preventative strategies in Indian Asian population
- - - - One parent gene is silenced
      - Affects several hundred genes in humans
        
        Many associated with disease
  - - - Imprinted allele being inactivated