Exam #5: Epigenetic Phenomena Flashcards
Define Epigenetics
Study of stable, heritable changes in gene expression without changing DNA sequence
De-novo Methylation
- “Writing”
- De-novo DNA methyltransferase
- Methylate cytosine in response to cell signaling
Maintenance Methylation
- “Copying”
- Maintenance Methyltransferase
- Copy the methylation pattern from an old DNA strand to a new DNA strand
CpG Islands
- Clusters of unmethylated CpG dinucleotides found close to the 5’ region of genes
- Methylation shuts down expression of neighboring genes
Hypomethylation & Genome Stability
- Expression of genes normally silenced by methylation
- Causes the reactivation of transposable elements, leading to somatic recombination & genomic instability
HP1
- Deacetylated histones are methylated
- Methylated histones bind HP1
- HP1 binds histone methylase, which allows chromatin inactivation to spread
Boundary Elements
- Chromatin barriers
- Separate active and inactive genomic regions
Imprinting
- DNA silencing that marks a chromosome as having come from the mother or father
- Occurs during gametogenesis
Prader-Willi Syndrome
- Imprinting problem
- Deletion on paternal chromosome 15
- Symptoms: Obesity, excessive food seeking, hypogonadism, & mental retardation
Angelmann Syndrome
- Imprinting problem
- Deletion on maternal chromosome 15
- Symptoms: Fascial dysmorphia, seizures, movement & gait disorder, and severe mental retardation
Parent Of Origin Effect
- Repression of genes is dependent on chromosomes parent of origin
- Female makes chromosomes look maternal
- Male makes chromosomes look paternal
Uniparental Disomy
- When a person receives two copies of a chromosome from one parent, and no copies from the other parent
- Can happen with trisomy & loss of surplus chromosome, if kept chromosomes are from the same parent
- Leads to problems with imprinting
Epigenetics & Cancer
- Global hypermethylation can cause cancer via silencing of tumor suppressor genes
- Hypomethylation can lead to genomic instability that initiates and propagates cancer
5-Azacytidine
- DNMT1 inhibitor
- Causes hypomethylation
- Counteracts malignancies associated with hypermethylation including Acute Myeloid Leukemia
How is epigenetic information stored?
On chromatin in the form of:
1) Methylation pattern of cytosine bases
2) Covalent modification of histones
What does the cell need to ensure the writing, retention, & correct interpretation of epigenetic information?
- Writers, enzymes that methylate cytosine in response to signals
- Copiers, enzymes that copy the methylation pattern from old DNA to newly synthesized DNA
- Readers, enzymes that recognize methylated stretches of DNA
“Writer Enzyme”
De-novo DNA methyltransferase (DNMT3 a&b)
“Copier Enzyme”
Maintenance methyltransferase (DNMT1)
CpG Dinucleotide Repats
- Commonly found in highly repetitive DNA, telomeres, centromeres
- Silenced by DNA methylation on cytosine
Hypermethylation
Shuts down the expression of genes close to CpG islands
Transposable Element
DNA sequence that can change its position within the genome
“Readers”
- Methylcytosine Binding Proteins
- Interact with repressors of transcription
- HDACs
Rett Syndrome
- X-linked dominant disorder
- Caused by defect in methylcytosine binding protein (MECP2)
- Normal development until ~6 months, then hypotonic, loss of hand control, autism-like with hand wringing, teeth grinding, & hyperventilation
What are the four ways that histones can be modified?
1) Acetylation
2) Methylation
3) Phosphorylation
4) Ubiquitination
HAT
- Histone acetyltransferase
- Acetylate histones
- Decrease binding to DNA
- Increase transcription
HDAC
- Histone deacetylase
- Increases histone binding affinity
- Silences transcription
X-Chromosome Inactivation
- In the X-chromosome inactivating center (XIC) there is a gene designated the inactive X-specific transcript (XIST)
- XIST RNA associates with chromosome and mediates inactivation of most of the chromosome
- Methylation causes inactivation
Beckwith-Weidemann Syndrome
- Uniparental disomy of chromosome 11
- Causes an overabundance of insulin-like growth factor 2
- Symptoms: kidney, adrenal, & liver problems resulting in hypoglycemia
SLE
- Systemic Lupus Erythematosus
- Abnormal T-cell function believed to be the root cause
- Genome of T-cells is hypomethylated & DNMT1 is reduced
- Leads to re-expression of silenced genes
