Epigenetics Flashcards
What is Epigenetic changes? What includes epigenetic changes
Inherited changes that are not coded in the DNA sequence. These include chromatin remodeling, histone modification and of course DNA methylation. These are inherited both mitotically and meiotically.
What is epigenomics
Study of the effects of DNA methylation, chromatin remodeling and histone modifications
When does along the genetic line the epigenetic changes are reset sort of
In the germ line cells. See the attached slide
What are the 4 major mechanisms of epigenetics
- DNA methylation - CpG Islands
- Histone modifications
- miRNAs and long non coding RNAs (lncRNAs)
- Chromatin remodeling - heterochromatin and euchromatin
All of these interactions interact!
How does the females turn off one of the X chromosomes
By RNA mediated gene silencing
What are the types of heterochromatin
It is of 2 types
- Constitutive: Regions of repeating DNA sequences like the centromeres
- Facultiative: Proteins coding regions of DNA that can be demethylated later (thats what he said)
What is the name of the enzyme that does the DNA methylation. Where does it put the methyl group at
DNA methyltransferase
The methyl group is at the 5 carbon cytosine
Where are CpG islands found
They are mostly found in the gene promoting regions. They can be methylated or unmethylated depending on if the gene is on or off
How does the heterochromatin form
The DNA methyltrasnferase comes in and methylates the CpG islands on the promoter region. This leads to HDAC to come and cause tight wounding of the histones to the DNA. We also have other substances that sit on these DNA sites, sterically hindring the RNA pol II from binding to the promoter region. All of these effects are additive and this results in the formation of 30 nm heterochromatin fibers
Where exactly are the histones acetylated
At the tails of the histones. These tails are sticking out so they are accessible by HAT or HDAC
What are some of the other types of histone modifications
Acetylation, ubiquitination, methylation etc etc
What are miRNAs and lnc RNAs used for
miRNAs are used for amplification, deletion, methylation, gene expression
lncRNAs are used for translocations and gene expression
What are the mechanism of action of miRNAs
- It can bind to mRNA in the center, forming a double helix structure, endonuclease chops this structure so have no functional mRNA
- miRNA can bind to polyA tail, endonuclease breaks down this mRNA
- miRNA can inhibit the proteins involved in translation by not allowing them to either bind to mRNA or move along the mRNA. This mRNA is also degraded
- miRNA can actually INCREASE translation too, somehow.
What does the lncRNAs do
It is important to know that they are much longer than the miRNAs, such that these lncRNAs can form hairpin structures
- They interact with DNA, can recruit proteins to increase transcription
- They can interact with DNA such that they can inhibit trasncription
- They can interact with mRNAs and change the splicing ratios of the proteins that are made from a single mRNA
- They can form a double helix structure with mRNA and can cause their degradation
- They can take away the miRNAs by forming structures with them so they fine tune protein translation
What does chromatin remodelling complexes do? What is required for their function
They position histones around the DNA with the help of ATP dependent nucleosome remodeling complexes. They non covalently place - histone octamers - around the DNA to have a nucleosome free or a nucleosome dense chromatin.
What are the classes of DNA modifications and histone modifications? What do they do
There are three main classifications:
- Writer: They identify the region of the DNA or histone, they can add for exmaple a methyl group to turn off trasncription
- Editors: involved in dynamic balance of writer, they can either modify or further reinforce the tag placed by writers to influence gene transcription
- Readers: they see the overall tags placed by the writers and readers and then determine if the gene is to be transcribed or not
What are Barr bodiesf
The sites in the cells of the female where one of the X chromsomes have been inactivated
What is XIC
X chromsome Inactivation Center
What is the diagram that he showed us regarding regarding X inactivation? What should we remember from it
It starts at the XIC and then travels in both directions from XIC to the entire chromosome
How does the silencing happen biomehcanically
XIS has basically a gene called Xist RNA that binds to the promoter region of this gene and carries out the X chromosome inactivation of almost all of the chromsomes.
This expression if global, all genes are silenced (this is not true)
This pattern is maintained through mitosis, not however through meiosis
How is the active X chromsome maintained to be active
Expression of Xist gene on the active X chromosome is blocked by an anti sense RNA called TSIX
What is an antagonist for TSIX
CTCF protein
How does the TSIX, XIST, ICE and CTCF ensure X chromosome activation and inactivation
When ICE is methylated, CTCF cannot bind to it. Therefore TSIX binds Xist gene and hence allows X chromosome to stay active.
When ICE is not methylated, CTCF comes in and binds to the ICE element. Now CTCF sterically hinders TSIX to bind to the Xist gene, since Xist gene is wide open, Xist RNA can come bind to the promoter region of this gene and carry out the X chromosome inactivation process
Does X chromsome involve only DNA methylation
No. It also requires histone deactylation by HDAC.
What is genomic imprinting
It is a mechanism by which epigenetic modifications are changed such that a gene is reversibly turned on or off depending on the sex of the parent
What are the characteristics of these genes
These are located in clusters, they have differential DNA methylation and histone modification, often code for (or somehow are associated with) non coding RNAs and antisense transcripts
How does genomic imprinting challenge mendelian genetics
It is different since mendelian genetics says
maternal parent genes = paternal parent genes
and
two working copies are associated with normal function
What disease is associated with genomic imprinting
Beckwith-Wiedemann syndrome
What are the phenotypic properties associated with this disease
Gigantism, macroglossia, viceromegaly and embryonic Wilms tumor
What is the core idea behind genomic imprinting
Due to the mechanism of X chromosome inactivation there are some genes that are inherited and activated in the offsprings.
X chromosme inactivation is one mechanism. There are many other mehcanism that causes specific alleles to be expressed in the offsprings that are also expressed in the parent
What is the biochemical cause of beckewith-weidmann syndrome
Results from excess of paternal or from loss of maternal contribution of genes. You have too much IGF2 gene that promotes embryonic growth potential. THe antagonist for IGF2 is H19 gene that is a tumor spressor RNA coding gene.
The cause of this disease can be point mutation or maternal translocation that can result in both of the genes being IGF2 resulting in gigantism
How is DNA methylation and cancer related
We shut down tumor supressor genes by hyper methylation.
Also you cannot methylate oncogenes that can result in tumor development
How are miRNA involved in cancer development and tumor inhibition. Name the specific example
There is an miRNA called let-7. It inhibits 3 genes: cMYC, HMGA2 and RAS. When let-7 is inhibited these genes contribute to the development of cancer.
Another example is miRNA-10b. It is needed for protein RHOC. However when miRNA-10b is increased there is more RHOC that leads to cancer development
What is the cloncal genetic model of cancer
