Transcript M10 Presentation - The Huttenhower Lab

Epigenetics
04/04/16
A single genome gives rise to distinct celltypes
Definition
• Epigenetics refers to changes in phenotype
(appearance) or gene expression caused by
mechanisms other than changes in the
underlying DNA sequence.
• These changes may remain through cell
divisions for the remainder of the cell's life and
may also last for multiple generations.
• However, there is no change in the underlying
DNA sequence of the organism.
• Non-genetic factors cause the organism's genes
to behave (or "express themselves") differently.
wikipedia
Epigenetic mechanisms
• Nucleosome positions
• Histone modification
• DNA methylation
Chromatin
• DNA is packaged into
chromatin.
• Nucleosome is the
fundamental unit of
chromatin. It wraps
146 bp DNA.
• The chromatin
structure is
hierarchical.
Felsenfeld and Groudine 2003
Nucleosome and histone modification
First layer chromatin structure
looks like “beads-on-a-string”.
A nucleosome is made of core
histone proteins.
The amino acids on the Nterminus of histones can be
covalently modified.
Felsenfeld and Groudine 2003
DNA methylation
DNA methylation
normally occurs at CpG
dinucleotide only and can
be inherited during celldivision.
Alberts et al. Molecular
Biology of the Cell
Aberrant DNA Methylation Pattern in
Cancer
Irizarry, Feinberg
Transcription regulation
•TF
•ACATGT
•RNA
ChIP-seq analysis
Peak Calling Methods
MACS (MACS2) – Liu Lab
Peakseq – Gerstein Lab
SPP – Park Lab
GEM – Gifford Lab
Epigenetic patterns are dynamic
Epigenetic patterns are dynamic
Epigenetic patterns are dynamic
Epigenetic patterns are dynamic
Epigenetic patterns are dynamic
Enhancers regulate gene expression
from a distance
Super-enhancers
Whyte et al., Cell 2013
Target super-enhancer in cancer
James Bradner
Chromatin state segmentation methods
• ChromHMM (Ernst&Kellis); Segway (Hoffman&Noble).
• Both are based on hidden Markov models (HMM).
chromatin state
histone mark
intensities
Assumptions
Markov
property:
Independent
obs:
Ernst et al., Nature 2011
•(Fine, Tishby 1998)
Chromatin Domain
•DO
chromHMM
diHMM
domain-level state
•Each domain-bin
corresponds to a
block of nuc-bins.
nuc-level state
Additional Assumptions
•Obs is determined
only by nuc-level
state
•Nuc-level transition
is domain dependent
•Domain-level transition
can only occur at the
end of a block
histone mark
intensities
depends on the domain-level state n
only when i is multiple of block
size
Marco et al. under review
•(Fine, Tishby 1998)
Comparison with chromHMM
•HHMM
•Dom
•Nuc
•chromHMM
Variation of genetic information may
predict disease risk
•wikipedia
Noncoding GWAS are enriched with
enhancer elements
Murrano et al., Science 2012
Identifying disease-relevant cell-types
Murrano et al., Science 2012
•Source: yewbiotech
BCL11A is a master regulator for
globin switch
•Bauer et al. 2012, Blood
BCL11A erythroid enhancer is required for HbF repression
•55 58 62
•Hardison and Blobel. Science 2013; Bauer et al. Science 2013
CRISPR/cas9 genome editing
Identifying critical sequences within BCL11A erythroid enhancer
Canver et al. Nature 2015
Identifying critical sequences within BCL11A erythroid enhancer
Identifying critical sequences within BCL11A erythroid enhancer
•essential
•dispensable
•Human
•largely dispensable
•largely dispensable
•essential
•partially dispensable
Species divergence at the BCL11A erythroid enhancer
•Mouse
Identifying critical sequences within BCL11A erythroid enhancer
Summary
• Epigenetics play an important role in gene
regulation in development and diseases.
• Epigenetic regulation provides mechanistic
understanding of disease associated
genetic variants.
• Predicted function of regulatory elements
can be experimentally tested by
CRISPR/cas9 genome-editing.