dna double helix
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Chromatin structure and cancer epigenetics. DNA double helix. Nucleosomes. 30 nm fiber. Chromosome. Felsenfeld & Groudine, Nature (2003). Chromatin structure and cancer epigenetics. Two areas of opportunity in physical science. Nucleosome Positioning. Molecular mechanics. - PowerPoint PPT PresentationTRANSCRIPT
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DNA double helix
Nucleosomes
ChromosomeFelsenfeld & Groudine, Nature (2003)
Chromatin structure and cancer epigenetics
30 nm fiber
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Chromatin structure and cancer epigenetics
Two areas of opportunity in physical science
Nucleosome Positioning
Epigenetic cell memory by nucleosome modification
•Molecular mechanics
•Dynamical systems
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The genomic code for nucleosome positioning
DNA double helix
Nucleosomes
Stretches of genomic DNA compete with each otherfor limiting numbers of nucleosomes
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Luger et al., Nature (1997)
Side view(Space filling representation)
Top view(Ribbon representation)
Nucleosomes inhibit regulatory protein binding
DNA is sterically occluded and highly distorted
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NF-KB; Chen et al., Nature 391: 410, 1998 GCN4; Ellenberger et al., Cell 71: 1223, 1992
Many gene regulatory proteins wrap completely around their DNA target sites
•Nucleosomes inhibit regulatory protein binding
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Deciphering the nucleosome positioning code
•In vitro selection of nucleosome-favoring DNAs
•Isolation of natural nucleosome DNAs
AATTTA
AATTTA
AA
TTTA
AATTTA
AATTTA
AA TT TA
AA
TT
TA
GC
GC
GC
GC
GC
GC
GC
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2,000 bpChromosome 14: 187000-207000
YPD in vivo
Gal in vivo
EtOH in vivo
Genes
In vitro
SLA2 ATG2 ZWF1 NAR1 LAP3 KEX2 YTP1
Model
Moore, Fondufe-Mittendorf, Gossett, Kaplan, Lieb, Segal & JW
In vitro nucleosome occupancy compared to in vivo
~100 million mapped nucleosomes
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Nucleosome positioning and epigenetic gene silencingof the MLH1 1a tumor suppressor gene
Lin, JC et al.,Cancer Cell 2007
DNA unmethylated, gene active
DNA methylated, gene inactive
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Nucleosome positioning and epigenetic gene silencingof the MLH1 1a tumor suppressor gene
Lin, JC et al.,Cancer Cell 2007
DNA unmethylated,Gene active
DNA methylated,Gene inactive
DNA de-methylationprecedes genereactivation
DNA unmethylated,Gene active
+ 5-aza-2’-deoxycytidine
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AATTTA
AATTTA
AA
TTTA
AATTTA
AATTTA
AA TT TA
AA
TT
TA
GC
GC
GC
GC
GC
GC
GC
Morozov, Fortney, Widom, & Siggia
•DNA is extremely sharply bent (~80 bp per turn)
•Sequence specific, but without base-specific contacts
•Stable nucleosome formation high cyclization probability
An elastic energy model for the sequence-dependent cost of DNA wrapping
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An elastic energy model for the sequence-dependent cost of DNA wrapping
AATTTA
AATTTA
AA
TTTA
AATTTA
AATTTA
AA TT TA
AA
TT
TA
GC
GC
GC
GC
GC
GC
GC
Morozov, Fortney, Widom, & Siggia
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Field et al. submitted
High resolution sequenced-based map of nucleosome positions in yeast
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Field et al. submitted
Favored and disfavored 5-mers in in vivo nucleosomes
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Felsenfeld & Groudine, 2003
The genomic code for nucleosome positioning
DNA
Nucleosomes
30 nm fiber
![Page 15: DNA double helix](https://reader035.vdocument.in/reader035/viewer/2022062723/56813bd0550346895da4f6bb/html5/thumbnails/15.jpg)
Chromatin structure and cancer epigenetics
Two areas of opportunity in physical science
Nucleosome Positioning
Epigenetic cell memory by nucleosome modification
•Molecular mechanics
•Dynamical systems
![Page 16: DNA double helix](https://reader035.vdocument.in/reader035/viewer/2022062723/56813bd0550346895da4f6bb/html5/thumbnails/16.jpg)
Dodd, IB, et al., Cell 2007
Epigenetic cell memory by nucleosome modification
Epigenetic states as attractors of dynamical systems
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DNA double helix
Nucleosomes
ChromosomeFelsenfeld & Groudine, Nature (2003)
Chromatin structure and cancer epigenetics
30 nm fiber
![Page 18: DNA double helix](https://reader035.vdocument.in/reader035/viewer/2022062723/56813bd0550346895da4f6bb/html5/thumbnails/18.jpg)