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Introduction to Epigenetics. Manoj Kannan BITS-Pilani & NCI-Frederick. Recap of some familiar terms in genetics. Gene Allele Genotype Phenotype Gene expression Gene silencing Genome. Genome expression. Well-established paradigm of how genetic information is transcribed and translated

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Introduction to epigenetics

Introduction to Epigenetics

Manoj Kannan

BITS-Pilani & NCI-Frederick


Recap of some familiar terms in genetics
Recap of some familiar terms in genetics

Gene

Allele

Genotype

Phenotype

Gene expression

Gene silencing

Genome


Genome expression
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 doesn’t explain!

  • Hence, it’s not just the genes, but how they are regulated that explains the phenotype variations


Here is a phenotype variation
Here is a phenotype variation…

What do you think is the basis?

But epigeneticallydifferent!

ALL THE MICE ARE GENETICALLY IDENTICAL!

May be from different parents?

Well, age difference…

Oh, okay - mutation in the pigment causing gene?


What is epigenetics
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


Three major epigenetic processes we will discuss today…

  • DNA Methylation

  • Histone modifications

  • RNA-mediated phenomena


Dna methylation
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


Distribution of dna methylation
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


Dna methyltransferases dnmts
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.


How does dna methylation affect gene transcription

Unmethylated (or hypomethylated) promoter allows gene transcription

Me-CpG binding proteins also preclude TF binding to the promoter region

Methylated CpGs block binding of TFs; hence, transcription blocked

How does DNA methylation affect gene transcription?

Other ways too…


Role of dna methylation
Role of DNA methylation transcription

  • 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


Three major epigenetic processes
Three major epigenetic processes transcription

  • DNA Methylation

  • Histone modifications

  • RNA-mediated phenomena


Structural organization of the genome
Structural organization of the genome transcription

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.


Structure of a nucleosome

~146 bp DNA transcription

Histone octamer core

Structure of a nucleosome


Post translational histone modifications
Post-translational histone modifications transcription

A = acetylation

M = methylation

P = phosphorylation

U = ubiquitination


Consequences of tail modifications
Consequences of tail modifications transcription

  • Higher order chromatin structure is affected

    eg. Addition of acetyl groups (-ve) neutralizes the positive charge on lysine

    => affinity of the histone to bind tightly to DNA is reduced

    => chromatin becomes less compact

    => 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


Enzymes catalyze these covalent tail modifications
Enzymes catalyze these covalent tail modifications transcription

  • 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



Crosstalk between dna methylation and chromatin modification

DNA methylation transcription

Self-reinforcing

repressive cycle

Histone deacetylation

Histone H3-K9 methylation

Crosstalk between DNA methylation and chromatin modification


Three major epigenetic processes1
Three major epigenetic processes transcription

  • DNA Methylation

  • Histone modifications

  • RNA-mediated phenomena


Rna interference rnai causes gene silencing
RNA interference (RNAi) causes gene silencing transcription

RNAi initiates heterochromatin formation in fission yeast and DNA methylation in plants.


Epigenetics in human disease
Epigenetics in human disease transcription

Association with various cancers – stomach, kidney, colon, pancreas, liver, uterus, lung and cervix

ICF syndrome

Fragile X syndrome

Angelman’s syndrome

Rett Syndrome

Coffin-Lowry Syndrome

HUMAN “EPIGENOME”

PROJECT




Epigenetics environment2
Epigenetics….Environment transcription

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 haven’t read the book yet!


References
References transcription

  • 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)


Thank you questions discussion
Thank you! transcriptionQuestions? Discussion?


If you want to read more about epigenetics
If you want to read more about Epigenetics… transcription

  • Chapter 10 of T.A. Brown’s 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/resources/res_epigenetics.dtl


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