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Epigenetic mechanisms in behaviour

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					Epigenetics and the brain;
  the nature of nurture?

         Anthony Isles
     Behavioural Genetics Group
         Cardiff University
            What is epigenetics?




“The transmission and perpetuation of information through
  cell division that is not based on the sequence of the
  DNA” (after Conrad H. Waddington c. 1942)
              What is epigenetics?
“The transmission and perpetuation of information through
  cell division that is not based on the sequence of the
  DNA” (after Conrad H. Waddington c. 1942)




  • Development and differentiation

  • Maintenance of cellular identity
  What is epigenetics?
Regulation, timing and level of gene expression




          Undifferentiated parent cell
         What is epigenetics?
      Regulation, timing and level of gene expression



XXXXXXXXXXX




Liver cell




                     XXXXXXXXXXX



                Undifferentiated parent cell
         What is epigenetics?
      Regulation, timing and level of gene expression



XXXXXXXXXXX                              XXXXX             XXXXX




Liver cell                                       Neural cell




              XXXXX                    XXXXX



                Undifferentiated parent cell
         What is epigenetics?
      Regulation, timing and level of gene expression



XXXXXXXXXXX                              XXXXX             XXXXX




                      Differentiation
Liver cell                                       Neural cell




              XXXXX                     XXXXX



                Undifferentiated parent cell
         What is epigenetics?
      Regulation, timing and level of gene expression



XXXXXXXXXXX                              XXXXX             XXXXX




Liver cell           Maintenance of              Neural cell
                     cellular identity




XXXXXXXXXXX                              XXXXX             XXXXX




Liver cell                                       Neural cell
          Molecular Mechanisms
• How is molecular control of gene expression exerted?


• DNA code remains unchanged
• Epigenetics are another layer of information laid on top of
  the DNA code
• Two main mechanisms:
    → DNA methylation
    → Histone (chromatin) modification
            Molecular Mechanisms
             – DNA methylation
• DNA sequence made up of 4 chemical bases; adenosine,
  guanine, tyrosine and cytosine (A,G,T,C)
• One base, cytosine is epigenetically modified by DNA
  methylation




• Encoded DNA information (i.e. ‘C’) remains the same
• Epigenetic code has changed…
• DNA methylation generally = suppression of gene activity
Molecular Mechanisms
– histone modifications


          • Histones; proteins around which
           DNA is bound
          • Histones are the main component
           of chromatin
          • Chromatin compacts and provides
           stability and structure to the DNA
Molecular Mechanisms
– histone modifications

     • Modifications of residues in the histone
       ‘tails’
     • >40 possible modifications
     • Modification alter 3-D structure and make
       DNA more, or less, accessible
     • Acetylation found in regions of increased
       gene expression
               Molecular Mechanisms
               – histone modifications

                          • Modifications of residues in the histone
                            ‘tails’
                          • >40 possible modifications
                          • Modification alter 3-D structure and make
                            DNA more, or less, accessible
                          • Acetylation found in regions of increased
                            gene expression
DNA-methylation and chromatin interact – differential recruitment of histones
The relevance of epigenetics
      to brain function
          Epigenetic mechanisms and
          neurodevelopment disorders
      Epigenetics important in cell differentiation and maintenance


                                   Aberrant DNA-methylation (MECP2)
• Rett syndrome

• Rubinstein-Taybi syndrome              Lack of Chromatin Binding Protein
                                         • Loss of Histone acetly-transferase
• Angelman/Prader-Willi


  Mutations in tightly regulated genes
  • Paternally/maternally imprinted genes on 15q11-q13
  • Also caused by loss of epigenetic control mechanism (i.e. no DNA loss)
          Environment and epigenetics


The transmission and perpetuation of information through
  meiosis and/or mitosis that is not based on the sequence
  of the DNA (after Conrad H. Waddington c. 1942)
                   Environment and epigenetics


The transmission and perpetuation of information through
  meiosis and/or mitosis that is not based on the sequence
  of the DNA (after Conrad H. Waddington c. 1942)


“…complex 'epigenetic' mechanisms, which regulate gene
  activity without altering the DNA code, have long-lasting
  effects within mature neurons.”
Tsankova, Renthal, Kumar & Nestler 2007 Nature Neuroscience Reviews 8: 355-367
              Environment and epigenetics
                 - encoding life events

                                            • Identical twins have identical DNA
                                            • Global differences in epigenetic status
                                              between twins increases with age

                                                Increased differences in methlyation
                                                • Green: areas of hypermethlyation
                                                • Red: areas hypomethylation
                                                • Yellow: equal levels of methylation




Fraga et al. (2005) PNAS 102, 10604-10609
              Environment and epigenetics
                 - encoding life events

                                            • Identical twins have identical DNA
                                            • Global differences in epigenetic status
                                              between twins increases with age

                                                Increased differences in methlyation
                                                • Green: areas of hypermethlyation
                                                • Red: areas hypomethylation
                                                • Yellow: equal levels of methylation


                                             Different life events give rise to different
                                                   patterns of epigenetic marks

Fraga et al. (2005) PNAS 102, 10604-10609
            Environment and epigenetics
        - programming of by early life events
• Female rats show varying levels of maternal care
   → Characterised by levels of licking and
      grooming of the pups
• Maternal care previously has long term non-
 genomic, effects on the offspring
   → Altered reactivity to stress
   → Altered expression of hippocampal GR
   → High licking and grooming in mother leads to
      high licking and grooming in offspring (and
      vice versa)
                                                     Nature neuroscience 2004 7:847-54
    Environment and epigenetics
- programming of by early life events




  • Altered DNA methylation
  • Altered recruitment of histones
                                      Nature neuroscience 2004 7:847-54
           Environment and epigenetics
       - programming of by early life events


• Childhood abuse leads to long term
  altered expression of Glucorticoid
  receptor (GR) expression




                  McGowan et al. Nature Neuroscience 12, 342 - 348 (2009)
           Environment and epigenetics
       - programming of by early life events


• Childhood abuse leads to long term
  altered expression of Glucorticoid
  receptor (GR) expression




                                                           • Corresponding changes in
                                                             methylation of the neuron
                                                             specific GR promoter,
                                                             NR3C1

                  McGowan et al. Nature Neuroscience 12, 342 - 348 (2009)
    Environment and epigenetics
- where genes and environment meet

  • Genome variation can effect gene function in several ways
      → Changes in encoded product (amino acid sequence)
      → Changes in regulatory regions that effect expression
    Environment and epigenetics
- where genes and environment meet

  • Genome variation can effect gene function in several ways
      → Changes in encoded product (amino acid sequence)
      → Changes in regulatory regions that effect expression

  • Epigenetics influence gene expression
  • Epigenetic change may interact with genetic variation
  • Provides the molecular link between genes and
    environment…
         Environment and epigenetics
     - where genes and environment meet

Low expressing MAO-A gene              Effects of 5-HTT gene variant on
variant interacts with childhood       depression moderated by care
maltreatment




                                        Science (2003) 301: 386-389

Science (2002) 297: 851-854


                                        PNAS (2004) 101: 17316-17321


Arch Gen Psychiatry (2004) 61:738-44

                                        Biol. Psych. 18 (2006) 59: 673-680
                                                                        Molecular Mechanisms
                                                                         – DNA methylation
Methylation of the reelin promoter in Schizophrenia




                                                                                                     • DNA methylation usually
                                                                                                      correlates with decreased
                                                                                                      gene expression
                                                                                                     • Generally occurs in regulatory
                                                                                                      regions of genes - promoters
                                                                                                      and enhancers - not in the
                                                                                                      coding regions


                                                      Grayson D. R. et.al. PNAS 2005;102:9341-9346

				
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posted:10/9/2011
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