Epigenitics - Johnson L1

Question 0

Waddington’s epigenetic landscape is an analogy for what?

Answer 0

A stem cell is like a high-energy state with the potential to go convert to any one of multiple low-energy specific cell states. Once it’s in a particular cell state (differentiated) it will stay there but has the “potential, in theory” to revert to its original high energy stem cell state; thus resetting its ability to convert to any one of multiple low energy states.

Question 1

What are the 4 defining characteristics of epigenetic phenomena?

Which one is the most promising for therapeutic potential?

Answer 1

1. Different gene expression/ phenotype but same genome
2. Inheritance through gene expression; passed on to next generation
3. Like a switch: On / Off
4. Edit-able or interconvertible

Therapeutic Potential - the interconvertability of epigenetic mark

Question 2

What are three specific examples of epigenetic phenomena (as discussed in lecture)?

Answer 2

1. Imprinting
2. Heterochromatin domains
3. X-inactivation
4. Histone marking
5. Centromere marking by histone variant CENP-A (for spindle attachment)
6. reinforcing feeback loops (trans-acting factors) in the cytosol that go to both cells upon division.

Question 3

How is DNA methylation inherited through cell division?

Answer 3

Maintenance Methyltransferase recognizes hemimethylated CpG’s and methylates the new strand to match the original methylation pattern.

If a CpG repeat is not methylated in the parent DNA, it will not receive a methylation from MMT after replication so the original pattern is preserved.

Question 4

Give three chemical modifications of DNA or Histones that can potentially be inherited.

Answer 4

1.  DNA methylation = Off
	Histone methylation = On or Off dep. on where on the histone
	as well as other marks on the histone
2.  Histone acetylation = On
3.  Histone phosphorylation
4.  Histone Ubiquitination

Question 5

Histone 3, Lysine (K) 4 methylation is a trxn activation or repression signal?

Answer 5

Activation.

*This one seems to show up every time I google search histone modification, so it may be good to know.

Question 6

Give an example of an epigenetic mechanism that occurs inside the nucleus.

Answer 6

DNA methylation occurs inside the nucleus. (oh boy, I hope so!)

Question 7

Give an example of an epigenetic mechanism that occurs outside the nucleus.

Answer 7

Inflammation can trigger cytosolic events that allow NF-kB to enter the nucleus and initiate trxn factors that lead to

1. Malignant Transformation
2. Cell Motility
3. Cancer Cell Growth
4. Self-Renewal of Tumor Initiation Cells —-> cancerous cell state passed on to the next generation of cells

The positive feedback loop (initiated by inflammation) is occurring in the cytosol and when the cell divides, the “loop” is passed on to both cells. New cells are reacting to the original inflam. event even if it is no longer present.

Question 8

Give an example of aberrant methylation of a gene (5meC) that can lead to disease.

What sort of therapy might be helpful?

Answer 8

Methylation of tumor suppressor genes (via aging, stress etc) will turn the TSG to be turned off. Now the cell more likely to turn malignant. –> Cancer

Therapies aimed at turning off the methylation of TSG’s may reset a cell to be non-cancerous.

Question 9

Give an example of an epigenetic combination therapy that has been shown to be effective in Refractory Small Cell Lung Cancer.

Answer 9

The goal is to turn a silenced tumor suppressor gene back ON Therapy is Inhibition of BOTH
DNA methyltransferase and Histone Deacetylase

Methylation of DNA = Off so disallow methylation
Histone Deacetylation = Off so disallow deacetylation

Question 10

Where in the DNA is the imprinting process “controlled” or “initiated”?

Answer 10

Imprinting centers - located within an imprinted gene; DNA elements that initiate the process of converting a gene from one epigenetic mark to another.

We know very little about this process.