Computational Epigenetics

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Computational Epigenetics

• The New Kid on The Block

Shen Jean Lim2, Tin Wee Tan2, Joo Chuan
Tong1,2   1Data Mining Department, Institute for
Infocomm Research 2Department of Biochemistry,
Yong Loo Lin School of Medicine, National
University of Singapore
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Epigenetics

• Study of mitotically and/or meiotically heritable
  changes in gene expression that are not encoded
  in the DNA sequence
• Mediated through chemical modifications of DNA
  and histones
• Alterations in chromatin structure that blocks or
  promotes transcriptional initiation

Source http//www.neb.com/nebecomm/tech_referenc
e/epigenetics/overviews.asp
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Levels of Chromatin Packing
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Histones
Source http//www.mun.ca/biology/scarr/Histone_P
rotein_Structure.html

• In eukaryotes, nuclear DNA is found assembled
  into chromatin by histones.
• Ocatameric histone core is made up of two
  molecules of each histone H2A, H2B, H3 and H4
• Packages approximately 147 base pair segments of
  nuclear DNA into nucleosome core particles (NCP).
  
• Histone H1 further condenses the DNA by binding
  the linker segments between the nucleosome core
  particles

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Histone Modifications

• Occur on flexible N-and C-terminal tails of the
  histones or within their globular folds in the
  nucleosome core
• Histone modifications act individually or
  combinatorially
• Alter chromatin structure
• Affect transcription, repair, replication and
  chromatin condensation and ultimately gene
  regulation

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Histone Modifications
Source http//chemistry.gsu.edu/faculty/Zheng/pi
ctures/nucleosome.jpg

• Enzymes involved in this process include DNA
  methyltransferases,histone deacetylases, histone
  acetylases, histone methyltransferases, histone
  demethylases etc

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Epigenetics Importance

• Epigenetic modulations are essential in many
  developmental processes
• Tissue formation, organ formation and
  allele-specific gene expression
• Changes in normal epigenetic patterns can
  deregulate patterns of gene expression, resulting
  in adverse clinical outcomes
• Psychiatric disorders, obesity , schizophrenia,
  Beckwith-Wiedemann syndrome, Alzheimers disease

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Epigenetics as a research field

• Highly combinatorial in nature due to the array
  of diverse control elements
• The human genome contains 23,000 genes that are
  active in specific cells at precise moments!!
• Post-translational modification may affect almost
  every solvent-accessible histone residue,
  allowing a high level of variability for signal
  transduction events

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Epigenetics as a research field

• Enormous combinatorial complexity requires large
  number of experiments for systematic studies
  (e.g. DNA methylation profiling)
• Large-scale initiatives for the systematic
  mapping of epigenomic and related data
• Alliance for the Human Epigenome and Disease
  (AHEAD) Task Force
• The ENCyclopedia Of DNA Elements (ENCODE) Project
  Consortium
• etc etc.

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Computational Epigenetics

• Huge quantity of experimental data generated
  requires appropriate bioinformatics
  infrastructure for meaningful analysis, modeling
  and prediction of DNA-protein interactions
• General and specialist databases
• Basic bioinformatics tools
• Sophisticated algorithms

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Computational Epigenetics

• General and specialist databases
• Basic bioinformatics tools
• Sophisticated algorithms

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Computational Epigenetics

• General and specialist databases
• Basic bioinformatics tools
• Sophisticated algorithms

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General databases

• Large amount of data relevant for epigenetic
  research are available in scientific literature,
  molecular databases and case reports.
• PubMed - primary source of data, provides
  high-level descriptions of biological entities
  and processes

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General databases

• Molecular databases

Databases described in the Nucleic Acids Research
online Molecular Biology Database Collection
(March 2009)
Total 1,078 molecular biology databases
Galperin MY, Cochrane GR. Nucleic Acids Research
annual Database Issue and the NAR online
Molecular Biology Database Collection in 2009,
Nucleic Acids Res 200937D1-4
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General databases

• Major molecular databases
• GenBank
• DNA Data Bank of Japan
• European Molecular Biology Laboratory
• serve as worldwide repositories for
  nucleotide sequences of different origins

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General specialist databases

• Databases for cell-, disease-, organism- and
  stage-specific gene expression
• General
• NCBIs Gene Expression Omnibus
• Specialist
• Gene Expression Nervous System Atlas
• StemBase
• Etc etc
• Allows for the identification of dynamic changes
  in gene expression in different cell types

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Epigenetics databases

• DNA methylation databases
• For the study of methylation content data and
  methylation patterns
• MethDB, MethPrimerDB
• Histone databases
• Information on histones and histone
  fold-containing proteins
• Important for research in the compaction and
  accessibility of eukaryotic and probably archaeal
  genomic DNA
• National Human Genome Research Institute
  (NHGRI)s Histone Database
• Cancer methylation databases
• Analyzing irregular methylation patterns that are
  correlated with various cancers
• PubMeth, MeInfoText

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Computational Epigenetics

• General and specialist databases
• Basic bioinformatics tools
• Sophisticated algorithms

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Basic Bioinformatics Tools

• Traditional sequence analysis tools allow for the
  inference of functional, structural, or
  evolutionary relationships between DNA or protein
  sequences
• E.g. ClustalW , BLAST (Basic Local Alignment
  Search Tool) software suite, BLAT (BLAST-Like
  Alignment Tool) and TreeView
• Diverse applications involving
• Homology searches of ortholog candidates for the
  KEGG/GENES database
• Predicting the secondary structures of histone
  deacetylases
• Homology modeling of DNA methyltransferases
• Optimizing the activities of histone deacetylase
  inhibitors

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Computational Epigenetics

• General and specialist databases
• Basic bioinformatics tools
• Sophisticated algorithms

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Sophisticated algorithms

• Computational models have been used extensively
  to support various epigenome mapping initiatives
• Identification of ChIP enrichment sites
  (ChIPOTle, TileMap, Ringo)
• Accurate mapping of short sequence reads
  generated by ChIP-seq to the reference genome
  (Blastn, BLAT)
• Algorithms for short-read assembly (QPALMA,
  AMOScmp)
• Data processing and quality assessment of
  bisulfite sequencing

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Major Research Areas in Computational Epigenetics
DNA Methylation
Histone Modifications
Cancer Informatics
Stem Cell Informatics
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Major Research Areas in Computational Epigenetics
DNA Methylation
Histone Modifications
Cancer Informatics
Stem Cell Informatics
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Research area DNA Methylation

• Modeling and prediction of DNA methylation
  patterns
• Prediction of methylation sites
• Focused on arginine and lysine methylations

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Research area DNA Methylation

• Epigenome prediction pipeline
• Integrates DNA methylation, polymerase II
  preinitiation complex binding, histone H3K4 di-
  and trimethylation, histone H3K9/14 acetylation,
  DNase I hypersensitivity and SP1 binding

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Research area DNA Methylation

• Limitation
• Lack of publicly available experimental data
  for model construction

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Major Research Areas in Computational Epigenetics
DNA Methylation
Histone Modifications
Cancer Informatics
Stem Cell Informatics
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Research area Histone Modifications

• Analysis, modeling and prediction of histone
  modifications in DNA sequences
• Machine-learning algorithms for locating
  histone-occupied and acetylation, methylation and
  phosphorylation positions in DNA sequences
• Discovery of activating and repressive histone
  modifications
• Structure-based techniques for the design of
  epigenetic inhibitors
• Functional annotation of epigenetic factors

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Research area Histone Modifications
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Major Research Areas in Computational Epigenetics
DNA Methylation
Histone Modifications
Cancer Informatics
Stem Cell Informatics
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Research area Cancer Informatics

• Identify novel methylation patterns that
  correlate with progression to malignancy
• CancerDip Consortium
• Abnormal DNA methylation within CpG islands

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Research area Cancer Informatics

• Classifying cancer subtypes based on epigenetic
  marks

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Major Research Areas in Computational Epigenetics
DNA Methylation
Histone Modifications
Cancer Informatics
Stem Cell Informatics
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Research area Stem Cell Informatics

• Study epigenetic marks in stem cells
• DNA methyltransferases and Polycomb/Trithorax
  group response elements (PRE/TRE) possess
  epigenetic signatures that are important for the
  differentiation of both human ES cells and germ
  line stem cells
• Stem cells are target cells for cancer
• Epigenetic changes may occur long before they are
  distinguishable as tumor cells

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Research area Stem Cell Informatics

• Analyses of up- and down-regulated gene clusters
• Provide valuable information on the effect of
  exogenous control on ES cell state in human

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Conclusion

• Realizing the full benefits of the
  informatics revolution will require significant
  advances in the efficiency of which new data is
  discovered, processed, interpreted and made
  accessible to researchers

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Conclusion

• Different bioinformatic and mathematical
  modeling approaches, in combination with advances
  in computational infrastructures, clearly could
  lead to improved understanding of
  posttranslational modifications at multiple
  levels of complexity, from the sub-cellular
  molecular level, to the cellular and systems
  level, and beyond