Introduction to DNA methylation and its impact on gene regulation

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Lecture Introduction to DNA methylation and its
impact on gene regulation Webpage http//www.mo
lgen.mpg.de/steinhof/vorlesung_ws0708/
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Lecture 7 DNMTs Summary
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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MeCP2 MBD1 MBD2 MBD3 MBD4
Can bind methyl CpG sequences
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Lecture Introduction to DNA methylation and its
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Lecture Introduction to DNA methylation and its
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What are the mechanisms of the DNMTs?
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Lecture Introduction to DNA methylation and its
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Lecture Introduction to DNA methylation and its
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Lecture Introduction to DNA methylation and its
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• How do DNMTs interfere with transcription?
• Crosstalk
• Histone
• Targeting i) chromatin
• ii) TFs
• iii) RNA

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Lecture Introduction to DNA methylation and its
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Lecture Introduction to DNA methylation and its
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Lecture Introduction to DNA methylation and its
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Lecture Introduction to DNA methylation and its
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Lecture Introduction to DNA methylation and its
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Hammond S, Bernstein E, Beach D, Hannon G (2000).
"An RNA-directed nuclease mediates
post-transcriptional gene silencing in Drosophila
cells". Nature 404 (6775) 293-6
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Reminder what is RNA interference Movie
http//www.nature.com/focus/rnai/index.html
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Lecture Introduction to DNA methylation and its
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Lecture Introduction to DNA methylation and its
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Summary
Cell Memory
Origin of methylation patterns
Regulation of Gene Regulation
Mutation
Chromosomal Stability
Mainly from Epigenetics, Allis et al, 2006,
Chapter 18
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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By the way .... CpG why a p?
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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A Mechanism of cell memory
Where does memory appear in biology? What does
it mean in terms of epigenetics?
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Lecture Introduction to DNA methylation and its
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A Mechanism of cell memory Hypothesis
In mammalian cells Cytosine methylation
predominantly at CpGs Mechanism of cell
memory? Holliday/Pugh 1975 and Riggs
1975 Observations Selfcomplementarity Therefore
pattern could be copied when cells
divide Replication -gt copy mechansim -gt
maintenance
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Lecture Introduction to DNA methylation and its
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A Mechanism of cell memory Hypothesis
Maintenance mechanism would exclusively methylate
CpGs basepaired with a methylated parental
CpG Nonmethylated CpGs would NOT be substrate
for this -gt Semiconservative replication like DNA
itself
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Lecture Introduction to DNA methylation and its
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A Mechanism of cell memory evidence for
heritable methylation patterns
Restriction enzymes
1978 Bird et al Symmetry
1981 plasmid remain methylated or unmethylated
over many cell cycles
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Lecture Introduction to DNA methylation and its
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A Mechanism of cell memory maintenance
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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A Mechanism of cell memory maintenance
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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Origin of DNA methylation patterns
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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Origin of DNA methylation patterns de novo
methylation in embryos
Cell transfections ES cells versus somatic cells
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Lecture Introduction to DNA methylation and its
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Origin of DNA methylation patterns CpG islands
and patterns
http//edoc.hu-berlin.de/dissertationen/hajkova-pe
tra-2002-09-16/HTML/chapter3.html
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Lecture Introduction to DNA methylation and its
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Origin of DNA methylation patterns dynamic
changes
BUT Vary in TIME and SPACE!
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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Origin of DNA methylation patterns dynamic
changes
TIME
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Lecture Introduction to DNA methylation and its
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Origin of DNA methylation patterns dynamic
changes
TIME
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Lecture Introduction to DNA methylation and its
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Origin of DNA methylation patterns active
demethylation
Space
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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Origin of DNA methylation patterns protection
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Lecture Introduction to DNA methylation and its
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Origin of DNA methylation patterns protection

• CpG islands are intrinsically unmethylated by the
  existing de novo DNA methyltransferases
• CpG islands are protected from methylation by the
  binding of factors which somehow exclude Dnmts
• CpG islands are maintained in a methylation free
  state with the aid of DNA methylases that
  actively remove methyl CpGs
• The atypical base composition and lack of
  methylation reflect abnormal DNA metabolism at
  these CpG islands
• Early embryonic transcription from a CpG island
  promoter is required to ensure that DNA
  methylation is excluded

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Lecture Introduction to DNA methylation and its
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Origin of DNA methylation patterns chromatin
structure
DNA methylation patters are determined by the
modification state of the underlying chromatin
RNAi
DNA Methylation
Chromatin mod
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Lecture Introduction to DNA methylation and its
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Regulation of gene expression
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Lecture Introduction to DNA methylation and its
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Regulation of gene expression evidence
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Lecture Introduction to DNA methylation and its
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Regulation of gene expression interference with
TFs
Binding maternal Igf2 promoterregion
CTCF
Nonbinding paternal Igf2 promoterregion because
methylated
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Lecture Introduction to DNA methylation and its
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Regulation of gene expression methyl binding
proteins
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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Regulation of gene expression methyl binding
proteins
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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Regulation of gene expression Rett syndrome
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Lecture Introduction to DNA methylation and its
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Regulation of gene expression
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Lecture Introduction to DNA methylation and its
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Mutation and stability
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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Mutation and stability dna methylation and
mutation
C
U
C
T
mC
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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Mutation and stability dna methylation and
chromosomal stability
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Lecture Introduction to DNA methylation and its
impact on gene regulation
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