epigenetics 12/05/07. epigenetic regulation is critical for cell differentiation
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Epigenetics
12/05/07
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Epigenetic regulation is critical for cell differentiation
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Gene imprinting
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More examples of epigenetic regulation
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Epigenetic mechanisms
• DNA methylation
• Histone modification
• Nucleosome positions
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DNA methylation
Alberts et al. Molecular Biology of the Cell
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Methylated genes are silenced
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Probable mechanisms for DNA methylation induced siliencing
• The DNA methylation marker directly interferes with TF binding.
• The DNA methylation marker is recognized by proteins that cause chromatin structure changes.
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1bp (0.3nm)
10,000 nm
30nm
11 nm
DNA in the nucleus is complexed with histones to
form nucleosomes
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Histone modification
Felsenfeld and Groudine, Nature, (2003)
AcetylUbiquitylMethylPhosphoryl
Histone tails can be covalently modified in multiple ways at multiple sites
Luger et al. Nature, (1997)
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How histone modfication is inherited
• Histone methylation marks may be inherited by local concentration.
• The exact mechanism for inheritance is unknown.
• Even if histone modification is inherited is not proved.
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Transcriptional regulation by chromatin
• Nucleosome positioning • Histone modification
TF
TF
TF target site
TF
TF
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DNA methylation
histone modification
chromatin
H3K9m
e3
H3K9me3
H4K16ac
HP1
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Epigenetic reprogramming during development
• Methylation marks are erased during cleavage. – Methylation of the maternal genome is actively
stripped within hours of fertilization.– Maternal genome is passively erased at a slower rate.
• de novo methylation after implantation. • Another round of demethylation during
differentiation.• DNA methylation is essential for development.
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Epigenetic reprogramming can reverse tumorgenesis
Hochelinger et al. Genes & Dev, (2004)
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Cancer and histone modification
Chin, Nature (1998)
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Cancer and chromatinBRG1, the motor component of the SWI/SNF chromatin complex, is mutated in multiple cell lines (Wong et al. 2000)
• prostate DU145;
• lung A-427;
• prostate TSU-Pr-1;
• lung NCI-H1299;
• breast ALAB;
• lung NCI-H1299;
• pancreas Hs 700T
•…
suggesting BRG1 may be a tumor repressor protein
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Genomic-view of epigenetic regulation
• How to detect genome-wide patterns of epigenetic markers?
• How do epigenetic factors regulate genome-wide gene expression?
• How is the distribution of genome-wide epigenetic markers regulated?
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1.Tile microarray– 20 bp offset, 50-mers– Chr III + 233 promoters
2.Hybridize– mononucleosomal DNA– vs naked genomic DNA
3.Compute
Log (mononuc/genomic)
Yuan et al., Science, (2005)
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Nucleosome positioning in yeast
MAT
MATa
MAT nucs
predictedpositioned nucs
literaturepositioned nucs
fuzzy nucs
MFA2 HIS3
CHA1 centromere
Yuan et al., Science, (2005)
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Average signal (aligned by ATG codon) shows regular pattern.
Stereotyped pattern
Aligned by ATG
95% CI
Distance to ATG
Log
2
Ra
tio
Yuan et al., Science, (2005)
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Transcription factor binding sites (TFBSs) are likely to be nucleosome-depleted
TFBSs tend to be nucleosome-depleted.
Motif sites that are unbound in our condition but bound in other conditions also tend to be nucleosome depleted.
Motif sites that are always unbound do not have nucleosome-depletion property.
Yuan et al., Science, (2005)
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Histone modification in yeast
Liu et al., PLoS Biology, (2005)
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Co-regulated histone modifications
Liu et al., PLoS Biology, (2005)
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Nucleosome positioning in human
Ozsolak et al., Nat Biotech, (2007)
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Histone modification in human
Guenther et al., Cell, (2007)
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Distinct histone modification pattern in Embryonic Stem (ES) cells
Gene
ES
Differentiated cell type 1
Differentiated cell type 2
Bernstein et al. Cell (2006)
H3K27M: repressiveH3K4M: active
Differentiated cell type n
ES cells contain both repressive and active markers
Differentiated cells contain either repressive or active markers but not both
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Euchromatin and heterochromatin
http://respiratory-research.com
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Large–scale chromatin domain
Rinn et al. Cell (2007)
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Large-scale chromatin domain
ENCODE, Nature, 2007
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Large-scale chromatin domain
ENCODE, Nature, 2007
Open Closed
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Large-scale chromatin domain
ENCODE, Nature, 2007
Open Closed
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DNA methylation in human
Eckhardt et al. Nat Gen. (2007)
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DNA-methylation pattern in human
Eckhardt et al. Nat Gen. (2007)
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Histone modification
Felsenfeld and Groudine, Nature, (2003)
AcetylUbiquitylMethylPhosphoryl
Histone tails can be covalently modified in multiple ways at multiple sites
Luger et al. Nature, (1997)
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Histone code hypothesis“… multiple histone modifications, acting in a combinatorial or sequential fashion on one or multiple histone tails, specify unique downstream functions …” ― Strahl and Allis,
Nature, (2000)
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• Integrative analysis using multiple genomic data resources
(sequence, gene expression, histone modification)
• Linear regression model
yi expression; Aij acetylation; Si promoter sequence
• Key is to estimate sequence dependent regulatory effects.
j
iiijji SfAy )(
Statistical assessment of the global impact of histone acetylation on gene expression
Yuan et al. Gen Bio (2006)
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Estimating sequence dependent regulation effects
Linear regression model with transcription factor binding motifs
Sij motif score
•Scan motif (MDscan, AlignAce)
•Filter out insignificant motifs (RSIR)
linear f(Si)
j
ij
ijjijji SAy
Yuan et al. Gen Bio (2006)
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Performance of the linear regression model
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Performance of the linear regression model
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Performance of the linear regression model
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Cumulative effect of histone acetylation
Test whether including quadratic interaction between different acetylation sites would improve model performance
quadratic interaction
j
ij jk
ikijjkj
ijjijji AASAy
p-value for quadratic interaction coefficients (jk)
statistically insignificant
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Reading List
• Strahl and Allis 2000;– Proposed histone code hypothesis
• Bernstein et al. 2007– An up to date review of epigenomics
• Yuan et al. 2005;– Nucleosome positions in yeast
• Yuan et al. 2006;– Statistical analysis of histone related gene
expression.