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Introduction to Epigenetics/Epigenomics

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1 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

2 Epigenetics 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.

3 Epigenetics Mechanisms
RNA Interference Gene Expression DNA Methylation Histone Modifications

4 DNA Methylation Hypomethylation Hypermethylation

5 Natural Roles of DNA Methylation in Mammalian System
Imprinting X chromosome inactivation Heterochromatin maintenance Developmental controls Tissue specific expression controls

6 DNA Methylation and Cancer
Robertson, Nature Reviews Genetics, Vol6, 597

7 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

8 Histone Modifications

9 Histone Modifications

10 Li e. al. (2007) Cell 128, 707

11 Histone Modifications in Relation to Gene Transcription
Li e. al. (2007) Cell 128, 707

12 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)

13 RNA Interference (RNAi)

14 siRNA Mediated Heterochromatin Maintenance

15 Technologies for Studying Epigenetics/Epigenomics
DNA Methylation Microarray or deep sequencing Irizarry et. Al. (2008) Genome Research 18(5):780

16 Bisulfite Sequencing

17 Bisulfite Sequencing

18 Global Interrogation of DNA Methylation using Microarrays
intron promoter exon 3’ 5’ Expression array Exon array Splicing array Promoter array Tiling array

19 Methylated/Unmethylated DNA Enrichment Methods
Restriction Enzyme Based Enrichment Methods Zilberman and henikoff (2007) Development 134, 3959

20 Methylated/Unmethylated DNA Enrichment Methods
Immunoprecipation Based Method Zilberman and henikoff (2007) Development 134, 3959

21 Hybridization to microarrays
Genomic DNA Enrichment for methylated DNA Labeling Labeling

22 Zilberman and henikoff (2007) Development 134, 3959

23 Technologies for Interrogating Epigenetics/Epigenomics

24 Technologies for Interrogating Epigenetics/Epigenomics
Histone Modifications ChIP-chip Antibody specific to one type of histone modification ChIP-seq Deep sequencing

25 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

26 Normalization The loess assumption is sometimes violated in ChIP-chip data

27 Normalization Cont. Quantile Normalization
Variance Stabilizing Normalization Probe Model Based Normalization

28 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

29 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.

30 Other Special Properties Cont.
Map high intensity probes back to the genome Locate TF binding location ChIP-DNA Noise Probes Chromosome

31 Smoothing

32 Peak Call Identify regions that show epigenetic changes.

33 Results Visualization

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

35 Software Packages and Comparisons
Johnson et al (2008) Genome Research 18: 393

36 Array Platform Comparisons
Johnson et al (2008) Genome Research 18: 393

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