Chromatin Remodeling by jRlV16S

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									Chromatin Remodeling
  *Cytosine Methylation*
                     Glossary
Epigenetic: Heritable changes in gene function, not caused
  by changes in the DNA sequence itself.

CpG (island): Stands for Cytosine (P-bond) Guanine.
  Refering to a small region of DNA with a high frequency
  of CG sequences with respect to other regions.

Heterochromatin: Highly condensed, and transcription-
  suppressed sections of DNA

Housekeeping Genes: Undergo active transcription for
  basic cell functions.
          Glossary – Enzymes

DNMT: DNA Methyltransferase -1, 3a, 3b, L

H3K9: Lysine 9 of Histone 3

Suv39h: histone methyltransferase (H3K9)

MeCP/MBD: Methyl CpG Binding domain protein.
          Glossary – Enzymes

HP1: Adaptor molecule.

HDAC: Histone DeAcetylating protein

PcG: Polycomb Group (and repressor complexes)

EZH2, Eed, Su212: series of proteins that
                  interact with PcG.
 Cytosine Methylation - Overview
• A method of gene regulation and suppression.
• Occurs when a methyl group is added to Carbon-
  5, of the pyrimidine ring via enzyme action.
• An Epigenetic process
• Methylation patterns are passed on to daughter
  strands during replication.
• Closely linked to histone modification
• Improper methylation can lead to the
  development of genetics disorders.
        Pattern of Inheritance

• Function of DNMT 1 as a Maintenance Enzyme

• CpG methylation only opposite another CpG which
  is already methylated.

• Non-methylated CpG pairs are not recognized by
  DNMT 1
Pattern of Inheritance




     (Molecular Biology Web Book: 2005)
   Identifying Methylation Sites
• Bisulfate sequencing

• Conversion of non-methyl. Cytosine to Uracil

• No change to methyl. Cytosine

• Sequenced through computer software
  identifying locations of methylation

• Two concentrations of methylation (low or high)
    DNA & Histone Modification
• Linkage between both DNA Methylation and
  Histone Modifications

• Histone Deacetylation, Methylation

• Which process is the initiator?

• Self-reinforced Model
   DNA & Histone Modification

Methylation:
   • The addition of methyl groups onto sites
     such as H3K9


Deacetylation:
   • The removal of acetyl groups from histone
   • Loses neutral charge on molecule
   DNA & Histone Modification

• Two opposite theories on which processes
  depends on which.

• Theory: Histone Mod. depends on DNA
  methylation – DNMTs, MBDs recruiting HDAC

• Theory: DNA methylation depends on Histone
  Mod. – Suv39h knockouts, requirements of a
  “reader” molecule. (Hp1)
        Self-Reinforced Model
• Based on the idea DNA methylation and Histone
  Modification have a ‘flow’ of information.

• Not a perfect model, does not fully explain gene
  silencing. However, a good explanation for
  permanent shut-off genes.
        Self-Reinforced Model
• DNMT binds to HP1, DNA is methylated close to
  H3K9 site.

• Causes MBD to bind with DNA, recruiting HDAC;
  H3K9 deacetylated.

• MBD also attracts H3K9 methyltransferase and
  an additional HP1; H3K9 is methylated.
Self-Reinforced Model
Other DNA and Histone connections
• H3K27 transcription repression (PcG, EED,
  EZH2 complex – “PRC” Polycomb Repressive
  Complex.

• PRC involvement in X-inactivation, Hox gene
  silencing, cancer metastasis

• H4K20 methylation. Lack of in some cancer cells
         Improper Methylation
• Retts syndrome – loss of function MeCP2 (mental
  retardation in young girls)

• ICF syndrome – DNMT3b mutation (abnormal
  immune system)

• Total DNMT knockout in mice: fetus dies before
  birth

• MBD2 assistance in hypermethylated cancer
  genes
                             References:
“A Simplified Description of DNA Methylation.” DNA Methylation Society. Oct 11, 2005.
      http://www.dnamethsoc.com/

Fuks, Francois. “DNA Methylation and histone modifications: teaming up to silence genes.”
      Current Opinion in Genetics. 15 (2005): 490-495

“[7] DNA Methylation and CpG Island.” Molecular Biology Web Book. 2005.
      http://www.web-books.com/MoBio/

“DNA Methylation.” Wikipedia, the Online Encyclopedia. 2005.
     http://en.wikipedia.org/wiki/DNA_methylation

“Epigenetics.” Wikipedia, the Online Encyclopedia. 2005.
      http://en.wikipedia.org/wiki/Epigenetic

“All HEPped Up about Methylation.” PLoS Biol 2(12): e433. November 23, 2004.
      http://biology.plosjournals.org/perlserv/?request=get-
      document&doi=10.1371/journal.pbio.0020433
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