Epigenetic phenomena Flashcards
What are the two ways in which DNA expression can be changed without changing the sequence?
Methylation/demethylation of DNA regions
Histone modifications
True or false: you can pass on epigenetic changes
True
What is epigenetics?
The study of stable, heritable changes that do not involve DNA changes
How is epigenetic information stored?
On the chromatin in the form of a methylation pattern of Cytosine bases
What three items does the cell need to maintain the correct interpretation of epigenetic information?
Writers
Copiers
Readers
What is the function of writers in epigenetic information?
Enzymes that methylation cytosine bases in response to signals
What is the function of copiers in epigenetic information
Enzymes that copy a methylation pattern from an old DNA strand to a new one
What is the function of readers in epigenetic information?
Enzymes that recognize methylated stretches of DNA and initiate silencing of the affected chromosomal regions
What are the three major regions of DNA that are silenced by methylation?
- highly repetitive DNA
- Telomeres
- Centromeres
Where are CpG regions usually found?
On the 5’ end of genes
True or false: methylation of CpG region has no effect on the surrounding DNA regions
False–they are also silenced
What is the action of DNMT3a and DNMT3b?
methylation of DNA (they are methyltrnsferases)
What is the enzyme that methylates the newly synthesized strand of DNA?
DNMT1
Why is DNA methylation useful for the repair machinery of the cell?
Can identify new/old strand based on methylation
What is the function of MBPs (methylcytosine binding proteins)?
Repress transcription of methylated DNA regions
What is Rett syndrome?
X-linked dominant disorder that is a defect in methyl-CpG binding proteins (failure to maintain chromatin silencing). This is perinatally lethal in boys
What are the four types of modification of histones?
Acetylation
Methylation
Phosphorylation
Ubiquitination
What is H2Az?
A variant of the histone H2A. CAn be exchanged for H2A to increase the transcription of silenced regions
Once a deacetylated region of histones has been established, what are the next three steps to spread the deacetylation/inactivation?
- Methylate the histones
- Methylated histones bind to HP1 proteins
- HP1 proteins bind histone methylases.
Histone modification takes place on what end of the polypeptide, the N or C terminus?
N-terminus
True or false: all of the four type of histone modifications can take place on a histone all at once
True
What are boundary elements?
Chromatin barriers where methylation stops
Why does the self propagating nature of DNA inactivation present a problem when chromosomal aberrations occur?
Because the silencing aspect of the transferred region can spread to part of the newly attached chromosome that should not be silenced
What is imprinting?
DNA silencing in a call that causes it to identify itself specifically, as well as whether it is paternal or maternal
How does imprinting occur?
DNA methylation and acetylation based on the imprinting center of each chromosome
A female will reprogram her gamete chromosomes to make them look like paternal or maternal chromosomes?
Maternal
A male will reprogram his gamete chromosomes to make them look like paternal or maternal chromosomes?
Paternal
How does the X chromosome become inactivated?
The XIST region on the X chromosome to be inactivated is trancribed, and the RNA recruits methyltransferases
True or false: all of the genes on the inactivated X chromosome are methylated/deactivated?
False– a few areas are not
True or false: phenotypes of a mutation can vary, depending on whether it is on the maternal or paternal chromosome?
True
What is uniparental dismony?
The condition where a person has only maternally or only paternally imprinted chromosomes
What is beckwith-Wiedemann syndrome?
When a child inherits both homologues of a portion of chromosome 11, resulting in overabundance of insulin-like growth factor 2 (leads to severe hyperglycemia)
There is a deletion of chromosome 15 on the PATERNAL chromosome. What is the disease? Symptoms?
Prader-Willi syndrome–obesity, food seeking behavior, MR
There is a deletion of chromosome 15 on the MATERNAL chromosome. What is the disease? Symptoms?
Angelman syndrome–unusual facial features, SZs, MR
How does hypermethylation cause CA?
Silencing a tumor suppressor gene
How does hypomethylation cause CA?
- Genomic instability leading to breakage and resealing double stranded breaks. This can change oncogenes or tumor suppressor genes
- Increase mutations in a CA already present
What is systemic lupus erythematosus?
an autoimmune disease where T cells genome is hypomethylated, and leads to the expression of silenced, endogenous retroviruses
What are the two classes of drugs that can be used to influence DNA methylation?
- Histone deacetylase inhibitors
2. DNA methyltransferase inhibitors (5-azacytidine)
What is 5-azacytidine used for?
Inhibits DMNT to reverse hypermethylation of tumor suppressor genes found in acute myeloid leukemia.
What is Rett syndrome?
X-linked dominant mutation in a MBP (MEP2), that leads to autism-like symptoms. (if in boys=death)
Once a deacetylated region of histones has been established, what happens next?
- Histones become methylated
- Methylated histones bind to HP1 proteins
- HP1 proteins bind to histone methyltransferases, propagating the effect
What is the cause for Lupus?
Hypomethylated T cell genes, and inactivation of DMNT1. This leads to the expression of endogenous retroviruses
HDAC inhibitiors do what to the genome? What is this used in?
promotes expression of silienced genes in chronic lymphocytic leukemia
How can hypermethylation be reversed?
DNMT inhibitor aza-cytidine
How can excessive chromatin silencing be reversed?
HDAC inhibitors
