Test 3 Epigenetics Flashcards
Basics of Epigenetics
Heritable changes in gene expression that occur without change to DNA sequence.
- Reversible
- Heritable environmental induction
- Paternal genome reset at fertilization
- Maternal genome reset gradually.
The 3 main epigenetic mechanisms?
- DNA methylation
- DNA methyltransferases ( - )
- Histone Modification
- Histone deacetylases ( - )
- Histone acetylases ( + )
- Acetylation relaxes genome so that transcription can occur.
- Histone methyltransferases ( - )
- Methyl - binding domain protein. MECP2
- RNA mediated epigenetic regulation
- Small RNAs
- Long non-coding RNAs, lncRNA
- Usually involved in facilitating DNA methylation or Histone modification.
Epigenetic influences?
Epigenetic imprinting and X-Chromosome inactivation
Role of DNMT3?
- De novo methylation of cytosine
- Occurs during gametogenesis
Role of DNMT1?
- Most common
- Responsible for maintaining methylation during replication.
- Adds them to the newly synthesized strands.
When does cytosine methylation usually occur?
When cytosine is followed by a guanine.
Enzyme responsible for DNA demethylation?
TET
Role of methylation?
Surpresses downstream regions.
Describe Histone Modification
- Covalent mods to Histone proteins, specifically how tightly the nucleosomes are packed.
- Tightly packed chromatin is not avaliable for gene expression
-
Heterochromatin
Nucleosomes are tightly packed together, highley enriched with 5-methylcytosine.
Euchromatin?
Less tightly packed allowing binding of RNA polymerase and regulatory proteins.
Once histone marks are set do they pass down to future daughter cells? If so what is the implication?
- Yes they are passed down
- This is why you cannot remake your entire body by using the DNA from a nose cell.
- It has already epigenetically differentiated.
Explain RNA - mediated Epigenetic regulation
- Small RNAs recruit proteins to transcript, that in turn recruit modifying enzymes.
- Long RNAs act as scaffolds for RNA-binding proteins.
- Chromatin modifying complexes
Two cycles heavily influenced by histone modification?
Circadian rhythm and menstrual cycle.
Example of long lasting effects of Epigenetic markers
Kids born to mothers during the Dutch famine winter, had a higher chance for diabetes and other metabolic diseases.
Theses markers were set during the pregnancy.
Explain X-Chromosome inactivation
- In homochromatic (XX) individuals
- Placental mammals - random X inactivation per cell.
- One is completely inactivated
- Females are chimeric due to different Xs being inactivated throughout body.
- One is completely inactivated
- Marsupials: imprinted X inactivation
- X that gets shut off is from one parent.
- Placental mammals - random X inactivation per cell.
3 systems of epigenetics in mammals
Heterochromatin maintenance
Developmental controls
Tissue specific expression controls.
What is imprinting?
Parent of origen dependent monoallelic DNA methylation or inactivation.
What is Xist?
- Xist is found on the non silenced X chromosome and
- Recruits: histone modifications and DNA methylations
What is Tsix?
Is the anti-sense gene of Xist, it blocks Xist on its own chromosome and upregulates Xist on the other chromosome.
What amino acids is commonly acetylated in Histone modification?
Lysine (K)
Epigenetic Mechanism of Disease:
Rett Syndrome
- Methyl CpG binding protein
- Generally de novo mutation
- Patients dont live long enough to have kids.
- Disease largely only seen in females, since males with this die in the womb.
Epigenetic Mechanism of Disease:
MTHFR
Methyl-ene-tetrahydro-folate reductase
- Linked to altered patterns of DNA methylation
- Increased risk for breast and colorectal cancer.
- Also effects reaction to medication.
Epigenetic Mechanism of Disease:
Give an example of Imprinting Disorder
- Two syndromes are located on the same chromosome (15) but which syndrome that occurs depends on if it came from the mother or father.
- Angelman syndrome: Maternal LOF
- Prader-Willi- syndrome - Paternal LOF
-
Beckwith-weidemann syndrome:
- Activation of lgf2 on maternal chromosome 11
- Gene is not silenced in the female, causing prenatal and post-natal overgrowth.
*
- Gene is not silenced in the female, causing prenatal and post-natal overgrowth.
- Activation of lgf2 on maternal chromosome 11
Example of a disease due to defects in Histone modifiation
Coffin-Lowry Syndrome
Profound intellectual deficiencies
Example of defect in methylation
Fragile X syndrome
Caused by CGG repeat in FMR1
What is an oncogene? and how does DNA methylation play a role with cancer?>
- Gene responsible for cell growth
- Hypomethylation : removing histones activates these genes causing cells to proliferate.
- Hypermethylation: Increased suppression of Tumor suppressor genes results in tumor growth, causing cancer.
How are epigenetic marks detected?
- Bisulfate sequencing
- If C is methylated then they stay Cs
- If they are unmethyled the Cs become Us and then Ts.
