Chromatin Remodeling by jRlV16S


									Chromatin Remodeling
  *Cytosine Methylation*
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

   • The addition of methyl groups onto sites
     such as H3K9

   • 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

• 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

• MBD2 assistance in hypermethylated cancer
“A Simplified Description of DNA Methylation.” DNA Methylation Society. Oct 11, 2005.

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.

“DNA Methylation.” Wikipedia, the Online Encyclopedia. 2005.

“Epigenetics.” Wikipedia, the Online Encyclopedia. 2005.

“All HEPped Up about Methylation.” PLoS Biol 2(12): e433. November 23, 2004.
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