Epigenetics 3 Flashcards
What is the test for a pluripotent cell?
Can form all 3 germ layers
What are the 3 germ layers?
Ectoderm, mesoderm, endoderm
What a progenitor cell?
A cell that proliferate but has restricted lineage
What are differentiated cells?
Post mitotic cell and so can no longer proliferate
What did waddingtons model imply?
That cells can not dedifferentiate - this is not the case
When did John Gurdon do his stuff?
1958 - tadpole somatic nucleus into xenopus occyte and made froggie
When was dolly the sheep?
1996
What Tf’s dedifferentiated somatic cells?
Oct3/4, KLF4, Sox2, c-MYC
What is used now instead of oncogenic c-Myc?
Tbx3
What are the epigenetic barriers for dedifferentiation?
DNA Methylation, chromatin modification
What intermediate was discovered that implicated that cytosines could be unmethylated?
5-hydroxymethylcytosine
What enzyme converts 5-methylcytosine to 5-hydroxymethylcytosine?
TET
What is the pathway from 5-methylcytosine –> carboxylcytosine?
5mC –> 5hmC –> formylcytosine –> carboxylcytosine
TET does all of it
What catalyses either formylcytosine or carboxylcytosine to Abasic site?
TDG
What occurs after Abasic formation?
Base excision repair
Other than base excision, how might carboxylcytosine be repaired to cytosine?
Decarboxylation - not comfirmed
Are TET and TDG required for reprogramming cells?
yes
What can replace in Oct4 in OSMK factors?
TET1
What can neomorphic mutations in isocitrate dehydrogenase lead to?
Accumulation of 2-hydroxy-glutarate
What are the downstream affects of 2-hydroxy-glutarate?
Inhibits TET and lysine demethylases (H3K9) - hence inhibits dedifferentiation
Can also inhibit succinate dehydrogenase ( causing build up of succinate and prevention of HIF hydroxylation, hence build up of HIF - oncogene)
80% of adult glioma brain tumours have mutations in what?
Isocitrate dehydrogenase
Often no TET mutation are found - brain maybe relies more on chromatin structure??
What do stem cells reexpress to adapt to microenvironment?
TET/IDH - a balancing act
New therapies are often now designed to target specifically the cancer stem cells. What is an issue with this?
Cells can often develop resistance.
e.g. T cells were reprogrammed so they can recognise cancer antigens - cells eventually just lost antigen from surface
How is MBDP used to prevent reprogramming as part of NuRD?
MBDP binds methyl groups on DNA and represses transcription
WDR5 (in trithorax complex) binds Oct4 recruiting WDR5 to what kind of genes?
Pluripotent genes. This leads to methylation of H3K4 promoting gene activation
How is UTX pro dedifferentiation?
It is a H3K27 demethylase which interacts with oct4, KLF4 and Sox2 to remove repressive mark H3M27me on pluripotency genes
Is MYC necessary for reprogramming?
No, it just accelerates the process
Which of the following in activating on the E-box promoter:
a) MAX-MAX
b) MYC-MAX
c) MAD-MAX
b) MYC-MAX
How might MYC-MAX be a good drug target?
Drug might mimic interaction and therefore prevent interaction
Is maintaining differentiation an active process?
Yes, we think so
What do lineage specific guardians do?
Maintain differentiation
What does lineage specific guardian Pax5 maintain?
B cells
What does lineage specific guardian Lola maintain?
Immature neurons
