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Introduction to Epigenetics/Epigenomics. Xiangqin Cui Department of Biostatistics University of Alabama at Birmingham. Workshop on Statistical Genetics and Genomics, Southern Regional Meeting in New Orleans, Feb 12, 2009. Epigenetics.

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introduction to epigenetics epigenomics

Introduction to Epigenetics/Epigenomics

Xiangqin Cui

Department of Biostatistics

University of Alabama at Birmingham

Workshop on Statistical Genetics and Genomics, Southern Regional Meeting in New Orleans, Feb 12, 2009

  • Epigenetics refers to the study of changes in the regulation of gene activity and expression that are not dependent on gene DNA sequence.
  • While epigenetics often refers to the study of single genes or sets of genes, epigenomics refers to more global analyses of epigenetic changes across the entire genome.
epigenetics mechanisms
Epigenetics Mechanisms

RNA Interference

Gene Expression

DNA Methylation

Histone Modifications

dna methylation
DNA Methylation



natural roles of dna methylation in mammalian system
Natural Roles of DNA Methylation in Mammalian System
  • Imprinting
  • X chromosome inactivation
  • Heterochromatin maintenance
  • Developmental controls
  • Tissue specific expression controls
dna methylation and cancer
DNA Methylation and Cancer

Robertson, Nature Reviews Genetics, Vol6, 597

dna methylation and other human diseases
DNA Methylation and Other Human Diseases
  • -- Imprinting Disorder:
    • Beckwith-Wiedemann syndrom (BWS)
    • Prader-Willi syndrome (PWS)
    • Transient neonatal diabetes mellitus (TNDM)
  • -- Repeat-instability diseases
    • Fragile X syndrome (FRAXA)
    • Facioscapulohumeral muscular dystroph
  • -- Defects of the methylation machinery
    • Systemic lupus erythemtosus (SLE)
    • Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome
histone modifications
Histone Modifications

histone modifications1
Histone Modifications

Histone Modifications and Human Diseases

Coffin-Lowry syndrome is a rare genetic disorder characterized by mental retardation and abnormalities of the head and facial and other areas. It is caused by mutations in the RSK2 gene (histone phosphorylation) and is inherited as an X-linked dominant genetic trait. Males are usually more severely affected than females.

Rubinstein-Taybi syndrome is characterized by short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes.It is caused by mutations in CREB-binding protein (histone acetylation)

rna interference rnai
RNA Interference (RNAi)

technologies for studying epigenetics epigenomics
Technologies for Studying Epigenetics/Epigenomics

DNA Methylation

Microarray or deep sequencing

Irizarry et. Al. (2008) Genome Research 18(5):780

Global Interrogation of DNA Methylation using Microarrays






Expression array

Exon array

Splicing array



Tiling array

methylated unmethylated dna enrichment methods
Methylated/Unmethylated DNA Enrichment Methods

Restriction Enzyme Based Enrichment Methods

Zilberman and henikoff (2007) Development 134, 3959

methylated unmethylated dna enrichment methods1
Methylated/Unmethylated DNA Enrichment Methods

Immunoprecipation Based Method

Zilberman and henikoff (2007) Development 134, 3959

hybridization to microarrays
Hybridization to microarrays

Genomic DNA

Enrichment for methylated DNA



technologies for interrogating epigenetics epigenomics
Technologies for Interrogating Epigenetics/Epigenomics


technologies for interrogating epigenetics epigenomics1
Technologies for Interrogating Epigenetics/Epigenomics

Histone Modifications


Antibody specific to one type of histone modification


Deep sequencing

epigenomics microarray data analyses
Epigenomics Microarray Data Analyses

Major difference between data generated in epigenomics study and expression study is at the utility of the information of probe location in the genome. The adjacent probes are often correlated.

Data Analysis steps:

  • Data normalization
  • Statistical Modeling
    • Modeling
    • Peak Finding
  • Results Visualization along the genome
  • The loess assumption is sometimes violated in ChIP-chip data
normalization cont
Normalization Cont.
  • Quantile Normalization
  • Variance Stabilizing Normalization
  • Probe Model Based Normalization
nomalization based on probe sequences
Nomalization Based on Probe Sequences
  • Model the probe behavior based on probe sequence for Affymetrix arrays

Log(PM) = nucleotide + NucleotideCount2 + log(probeCopy#) + ε

  • Model the probe behavior based on probe GC content for long oligo arrays

For each group of probes with a give GC content, the background follows a normal distribution (µ,σ2).

Johnson et al (2006) PNAS 103, 12457; Song et al (2007)Genome Biology.8:R178

other special properties
Other Special Properties

GC content affects antibody binding to methylated DNA--- need for normalization against GC content.

Pelizzola et al (2008) Genome Research, 18, 1652.

other special properties cont
Other Special Properties Cont.
  • Map high intensity probes back to the genome
  • Locate TF binding location





peak call
Peak Call
  • Identify regions that show epigenetic changes.

Ji et al (2008) Nature Biotechnology. 26, 1293

software packages and comparisons
Software Packages and Comparisons

Johnson et al (2008) Genome Research 18: 393

Array Platform Comparisons

Johnson et al (2008) Genome Research 18: 393