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

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Chromatin remodeling

Chromatin Remodeling

*Cytosine Methylation*


Glossary
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
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 enzymes1
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
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
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


Chromatin remodeling

Pattern of Inheritance

(Molecular Biology Web Book: 2005)


Identifying methylation sites
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
DNA & Histone Modification

  • Linkage between both DNA Methylation and Histone Modifications

  • Histone Deacetylation, Methylation

  • Which process is the initiator?

  • Self-reinforced Model


Methylation

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

Methylation:

Deacetylation:


Dna histone modification1
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
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 model1
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.



Other dna and histone connections
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
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
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


Questions comments

Questions? Comments?

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