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Introduction to Epigenetics

• Manoj Kannan
• BITS-Pilani NCI-Frederick

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Recap of some familiar terms in genetics
Gene Allele Genotype Phenotype Gene
expression Gene silencing Genome
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Genome expression

• Well-established paradigm of how genetic
  information is transcribed and translated
• Human genome project has given plenty of data,
  which is still being mined for useful information
• An estimated 140,000 proteins in the human body
• Different cells express a different subset of
  proteins
• Yet almost all cells have the same genomic
  sequence comprised of just under 25,000 genes
• 25,000 genes ? 140,000 proteins?? Simple math
  doesnt explain!
• Hence, its not just the genes, but how they are
  regulated that explains the phenotype variations

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Here is a phenotype variation
What do you think is the basis?
ALL THE MICE ARE GENETICALLY IDENTICAL!
But epigenetically different!
May be from different parents?
Well, age difference
Oh, okay - mutation in the pigment causing gene?
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What is Epigenetics?

• Study of heritable changes in gene function that
  do not involve changes to the nucleotide sequence
  of DNA
• When a cell undergoes mitosis or meiosis, the
  epigenetic information is stably transmitted to
  the subsequent generation
• Epigenetic controls add an extra layer of
  transcriptional control

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Three major epigenetic processes we will discuss
today

• DNA Methylation
• Histone modifications
• RNA-mediated phenomena

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DNA Methylation
Most well-studied epigenetic tag/mark best
understood epigenetic cause of disease Conserved
across various kingdoms of life
SAM S-adenosylmethionine SAH
S-adenosylhomocystine
So, G, A, T, C. and the fifth base, mC in
mammalian genome
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Distribution of DNA methylation

• In mammals, in the context of CpG dinucleotides
  (plants have other types too)
• Methylated CpGs are associated with silenced DNA,
  eg. Transposons, inactive X chromosome, imprinted
  genes
• CpG islands, associated with promoters of 40
  of mammalian genes, are generally free of
  methylation
• eg. housekeeping genes, tissue-specific genes

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DNA methyltransferases (DNMTs)
2 major classes of enzymes in mammalian systems
De novo methylases
Maintenance methylase
Mouse knockouts of these genes tell us they are
necessary for the survival and proper development
of the organism.
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How does DNA methylation affect gene
transcription?
Other ways too
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Role of DNA methylation

• Tight control for maintaining gene silencing
  (vertebrate genes are less leaky compared to
  bacterial)
• Transcriptional silencing of transposons (genome
  defense model)
• Genomic imprinting one of the alleles of a gene
  is silenced, depending on the parent of origin

• X inactivation all but one of the X
  chromosomes in
• female is inactivated methylation of the
  inactive X copy

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Three major epigenetic processes

• DNA Methylation
• Histone modifications
• RNA-mediated phenomena

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Structural organization of the genome
Unless the genome is accessible by the
transcription machinery of the cell, the genome
cannot be functional! Hence, the utilization of
the biological information in the genome is
dependent on the chromatin organization.
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Structure of a nucleosome
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Post-translational histone modifications
A acetylation M methylation P
phosphorylation U ubiquitination
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Consequences of tail modifications

• Higher order chromatin structure is affected
• eg. Addition of acetyl groups (-ve) neutralizes
  the positive charge on lysine
• gt affinity of the histone to bind tightly to
  DNA is reduced
• gt chromatin becomes less compact
• gt transcription of the associated gene is
  favored
• Vice versa for deacetylation (the gene is
  repressed)
• Other proteins are attracted to these sites of
  modifications.which, in turn, affect gene
  expression

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Enzymes catalyze these covalent tail modifications

• Histone Acetyl Transferases (HATs)
• function as large, multiprotein complexes, eg.
  SAGA, ADA complexes (yeast), TFTC complexes
  (humans) associated with transciptional
  activation.
• Histone Deacetylases (HDACs)
• part of multiprotein complexes, eg.Sin3, NuRD
  associated with transcriptional repression.
• Histone Methyl Transferases (HMTs)
• Histone Demethylases

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Comparing chromatin types
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Crosstalk between DNA methylation and chromatin
modification
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Three major epigenetic processes

• DNA Methylation
• Histone modifications
• RNA-mediated phenomena

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RNA interference (RNAi) causes gene silencing
RNAi initiates heterochromatin formation in
fission yeast and DNA methylation in plants.
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Epigenetics in human disease
Association with various cancers stomach,
kidney, colon, pancreas, liver, uterus, lung and
cervix ICF syndrome Fragile X syndrome Angelmans
syndrome Rett Syndrome Coffin-Lowry Syndrome
HUMAN EPIGENOME PROJECT
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Epigenetics.Environment
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Epigenetics.Environment
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Epigenetics.Environment
And Consciousness!
The Biology of Belief Unleashing the Power of
Consciousness, Matter and Miracles is a recent
book in the market on epigenetics!
Disclaimer I havent read the book yet!
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References

• Genomes (3/E) T.A. Brown
• Molecular Biology of the Cell (4/E) Bruce
  Alberts, et al.
• Human Molecular Genetics (2/E) Strachan Read
• Developmental Biology (7/E) - Gilbert
• NCBI Bookshelf - free online books!
  (http//www.ncbi.nlm.nih.gov/entrez/query.fcgi?db
  Books)

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Thank you!Questions? Discussion?
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If you want to read more about Epigenetics

• Chapter 10 of T.A. Browns Genomes (3/E),
  entitled Accessing the Genome is an good place
  to start
• Special issue of Science 10 Aug. 2001 has a bunch
  of excellent articles written by pioneers in the
  field. (slightly dated, but still relevant)
• Science Functional Genomics Resources
  Epigenetics (portal hosted by the Americal
  journal, Science) gives a series of articles
  published in the field, and also a list of useful
  websites
• http//www.sciencemag.org/feature/plus/sfg/resour
  ces/res_epigenetics.dtl