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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 Presentation
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DNA double helix
Nucleosomes
ChromosomeFelsenfeld & Groudine, Nature (2003)
Chromatin structure and cancer epigenetics
30 nm fiber
Chromatin structure and cancer epigenetics
Two areas of opportunity in physical science
Nucleosome Positioning
Epigenetic cell memory by nucleosome modification
•Molecular mechanics
•Dynamical systems
The genomic code for nucleosome positioning
DNA double helix
Nucleosomes
Stretches of genomic DNA compete with each otherfor limiting numbers of nucleosomes
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
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
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
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
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
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
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
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
Field et al. submitted
High resolution sequenced-based map of nucleosome positions in yeast
Field et al. submitted
Favored and disfavored 5-mers in in vivo nucleosomes
Felsenfeld & Groudine, 2003
The genomic code for nucleosome positioning
DNA
Nucleosomes
30 nm fiber
Chromatin structure and cancer epigenetics
Two areas of opportunity in physical science
Nucleosome Positioning
Epigenetic cell memory by nucleosome modification
•Molecular mechanics
•Dynamical systems
Dodd, IB, et al., Cell 2007
Epigenetic cell memory by nucleosome modification
Epigenetic states as attractors of dynamical systems
DNA double helix
Nucleosomes
ChromosomeFelsenfeld & Groudine, Nature (2003)
Chromatin structure and cancer epigenetics
30 nm fiber
