Exploring Your Genome
Week 9 : EpigenomicsLecture 1: Introduction
Epigenome
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The genome is a sequence of nucleotides that istransmitted to the next generation
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The epigenome is the unique collection of modifications tothe nucleotides and associated proteins
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These modifications control access to the genome itself
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The epigenome is another level of genetic information
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“Epi” is Greek for on, above, near
The epigenome is the answer to manybig questions
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How does one genome result in so manydifferent cells and developmental stages?
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How can two people with the same exactgenome (twins) develop radically differentfunctional outcomes (phenotypes)?
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How can environmental exposure inparents lead to heritable, but non-nucleotide, changes in future generations?
Epigenomics: The Next Frontier
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Building on the Human Genome Project
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Epigenome refers to the genome-widedistribution of all modifications tochromatin in a cell
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Epigenetics is the study of heritablechanges in gene function that are not due toa change in DNA sequence
differentphenotypes, same genotype)
First, let’s review Chromatin
Chromatin is the complex of DNA and itsassociated proteinsThe proteins are mostly histones
Chromatin in Eukaryotic cells
DNA is packed by wrapping around histone proteins
Packed DNA and histones formnucleosomes
Histone proteins have short “tails”DNA in the densely packed state is not usually transcribedbecause the transcriptional machinery cannot access theDNADNA packing is a method of gene expression control: packedDNA = unreadable genes; open DNA = readable genesEpigenetic marks are modifications that are made to the DNAor to the histonesThe modifications can be proteins or chemical groups. Theyattach to the nucleotides directly or to the histone tails
Epigenetic marks
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The marks, or modifications, occur normallythroughout a lifetime
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The marks help to control access to thegenes - turning genes on/off throughdifferent stages of development anddifferentiation
Main
types
of epigenetic mechanisms
1.Methylation of Cytosines2.Histone tail modification3.Chromatin binding proteins4.Non-coding RNAs
There are other types, but these are the main ones.Discovering new mechanisms of epigenetic control is aHOT area of research.
1. Methylation
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The best known and best studied type of epigeneticmodification
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Methylation of DNA has been studied for years
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DNA and histones can both be methylated
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Used as method to regulate gene expression
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Typically, methylation of DNA blocks transcription andrepresses expression
Methylation
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Cytosines in CG rich regions are the targets of methylation (CGCGGGCCGCCGC)
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CG rich regions are near mammalian genes
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Methyl group is added to cytosines
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Methylated cytosine prevents gene expression byblocking access of transcriptional machinery or bycondensing the DNA
2. Histone Modification
Histone tails are targets of modification.Chemical groups attach to the tails and helpto repress or activate transcription of DNA
Until recently, these twomechanisms of epigeneticswere the only onesstudied. There has beena boom in epigeneticresearch in the past fewyears.
3. Chromatin binding proteins
There are proteins thatbind to the epigeneticmarks like methylatedbases and help to repressor activate transcription.
4. Non-coding RNA
Non-coding RNAs are small RNAsequences that do NOT code forproteins. They were recently discoveredin the HG. Remember, that much of theHG is transcribed into RNA but nottranslated. Perhaps the “Junk” DNA ispart of the epigenetic mechanism. Non-coding RNAs have been identified ashelping to keep DNA in a tightly woundstructure.Non-coding RNAs playa role in X-inactivation. Here, theXist RNA coats the Xchromosome to keep itinactive.
Normal Epigenetic Roles
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X-inactivation
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Cell differentiation
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Imprinting
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Gene regulation in response toenvironmental factors
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