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Computational Approaches in Epigenomics. Guo-Cheng Yuan Department of Biostatistics and Computational Biology Dana-Farber Cancer Institute Harvard School of Public Health. BIO506, Jan 11 th , 2010. Definition.

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slide1

Computational Approaches in Epigenomics

Guo-Cheng Yuan

Department of Biostatistics and Computational Biology

Dana-Farber Cancer Institute

Harvard School of Public Health

BIO506, Jan 11th, 2010

definition
Definition
  • Epigenetics refers to changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence.

wikipedia

epigenetic mechanisms
Epigenetic mechanisms
  • Nucleosome positions
  • Histone modification
  • DNA methylation
slide4

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

slide5

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 N-terminus of histones can be covalently modified.

Felsenfeld and Groudine 2003

dna methylation
DNA methylation

DNA methylation normally occurs at CpG dinucleotide only and can be inherited during cell-division.

Alberts et al. Molecular Biology of the Cell

why do we care
Why do we care?
  • Epigenetics is an extra layer of transcriptional control.
  • Epigenetics plays an important role in development.
  • Epigenetic mechanisms can cause cancer and other diseases.
  • Epigenetic patterns are reversible and can be influenced by environments.
our goals
Our goals

Characterize cell-type specific epigenetic states

epigenonic data

TF binding

Elucidate epigenetic targeting mechanism

Computational model

microarray

DNA sequence

Understand epigenetic regulation in cell differentiation

Epigenetic signature of diseases

chromatin domains
Chromatin domains

chromatin loops

Intrachromosomal interactions

large-scale histone modification patterns

targeting mechanism for epigenetic factors
Targeting mechanism for epigenetic factors

Nucleosome positions

Histone modification pattern

an n score model to prediction nucleosome positions

Dinucleotide Frequency Signal

Wavelet Basis

Signal Decomposition

E1

E2

E3

An N-score model to prediction nucleosome positions

Wavelet Energy

Yuan and Liu

polycomb targets developmental genes in es
Polycomb targets developmental genes in ES

expressed

Oct4

Nanog

Sox2

Polycomb

repressed

Kim et al. 2008

Boyer et al. 2006

slide16

A computational model: BART

BART is a Bayesian average of regression trees

Motif A

Motif B

Motif C

NO

YES

NO

YES

NO

YES

Chipman et al. 2007

overall prediction accuracy

Propensity score

Number of cell-types in which the gene is targeted

Overall prediction accuracy

testing data ROC

AUC = 0.82

all factors

5 factors

CpG

random

Spring Liu; Zhen Shao

an integrated network

+

Hox

Polycomb

+

Hox

Dnmt1

cell-type B

cell-type A

An integrated network

TF network

Jess Mar

future directions
Future directions
  • How do genetic and epigenetic factors work together to regulate cell-type specific gene expression?
  • How does the integrated regulatory network change across cell-types?
  • Are there epigenetic signatures associated with common diseases and if so what role do they have?
acknowledgment
Acknowledgment
  • Jessica Larson
  • Yingchun (Spring) Liu
  • Zhen Shao
  • John Quackenbush Lab
    • Jess Mar
  • Stuart Orkin Lab
    • Xiaohua Shen
    • Jongwan Kim
  • Steve Altschuler
  • Ollie Rando
  • Jun Liu
  • Claudia Adams Barr Program