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SCRA > 6. the molecular regulation of stem cell fate > Flashcards

6. the molecular regulation of stem cell fate Flashcards

1
Q

what is epigenetics?

A

DNA and chromatin modifications that do not alter the primary nucleotide sequence

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2
Q

what are histone modifications?

A

covalent modifications made to histone tails

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3
Q

what does HDAC do?

A

HDAC removed the acetyl group from histones

this promotes gene silencing as it promotes the formation of heterochromatin

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4
Q

what does HAT do?

A

HAT adds acetyl group to histones

this promote gene activation as it promotes the formation of euchromatin

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5
Q

what type of genome modification is most easily changed?

A

histone modification

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6
Q

what DNA residue is methylated?

A

cysteine

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7
Q

what enzyme adds methyl groups to DNA?

A

DNA methyl-transferases

Dnmt1, Dnmt2, Dnmt3

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8
Q

what happens to the methylation pattern when a cell replicates?

A

it is inherited

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9
Q

where are CpG islands found?

A

surrounding genes

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10
Q

what is DNA methylation associated with?

A

silencing genes

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11
Q

what treatment can be use to determine what residues are methylated and how does it work?

A

Bisulfite treatment

  • this converts cysteine to uracil
  • methylated cysteines are protected
  • sequence DNA
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12
Q

describe the epigenetics of house keeping genes

A
  • DNA is in-methylated

- euchromatin

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13
Q

what is the chromatin of an embryonic stem cells like?

A

euchromatin

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14
Q

when a cell differentiates, what occurs to its epigenetics?

A
  • genes of certain lineages that the cell is never going to express are silenced
  • they are methylated and stored as heterochromatin
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15
Q

what are required in order to bring a cell back to pluripotency?

A

chromatin remodellers and DNA methyl-transferases

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16
Q

what is expressed in high levels in LT-HSC (and not further down the lineage) and what happens when this is knocked out?

A

Dnmt3a

differentiation is obstructed

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17
Q

competitive transplantation was carried out with KO LT-HSC, describe how this was done

A
  • mice with Mxl-Cre crossed with floxed Dnmt3a, BM transplanted into lethally irradiated WT mouse
  • WT and KO cells genetically marked so they can be followed and transplanted 1:1
  • pIpC added to induce deletion
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18
Q

what was the result of this competitive transplantation?

A
  • more Dnmt3a KO HSC were seen in peripheral blood than WT HSC
  • KO HSC show different distribution of progeny than normal (more B cells and less T cells)
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19
Q

what was concluded from the competitive transplantation?

A

larger number of HSC seen in peripheral blood when Dnmt3a KO as differentiation is being blocked

20
Q

what was seen in the proteome of Dnmt3a KO HSCs?

A
  • genes for multipotency and HSC genes were expressed at much higher levels than WT
  • genes for differentiation expressed at lower levels than WT
21
Q

what was seen in the genome of these Dnmt3a KO HSC?

A

multipotency genes that are methylated in WT HSC are un-methylated in KO

22
Q

name four types of genes that are linked to stemness and so are expressed at high levels in stem cells

A
  1. cell cycle inhibitors
  2. chromatin remodellers
  3. telomerase
  4. DNA repair genes
23
Q

what genes are expressed at low levels in stem cells?

A

genes of differentiation are expressed in low levels so that stem cells are poised to differentiate

24
Q

why are cell cycle inhibitors expressed at high levels in stem cells?

A

to maintain quiescence

25
Q

why are chromatin remodellers expressed at high levels in stem cells?

A

to maintain chromatin in an open state

26
Q

why is telomerase expressed in high levels in stem cells?

A

to maintain telomere length when stem cells replicate

27
Q

name a disease that affects the bone marrow and what is it caused by?

A

Fanconi anaemia is caused by defects in DNA repair which leads to increased cell cycle arrest in stem cells and progenitors

28
Q

what did the transcriptomic analysis of lots of stem cells during an injury response show?

A

there is lots of variation between stem cells which becomes even more obvious during an injury response

29
Q

describe the diffusion map which includes multiple different types of cell populations

A
  • each cells transcriptome has a 3D position on the diffusion map
  • cells with similar transcriptomes are close to each other
30
Q

describe pseudo time on the diffusion map

A

the diffusion map represents a journey through time as the cell differentiates

31
Q

describe pseudo space on the diffusion map

A

in a tissue as cell that is derived from another cell will be close in the tissue

32
Q

why do we use the word pseudo when referring to the diffusion map?

A

because we cannot actually see this process happening

33
Q

what are microRNA?

A

non-coding RNA that is involved in the post translational regulation of gene expression

34
Q

in addition to transcription factors, what else may regulate differentiation of a stem cell?

A

microRNA expression

35
Q

what can the deletion of TF in stem cells lead to?

A
  • deletion of certain lineages

- reduction in stem cell self-renewal

36
Q

what can over expression of certain TF in stem cells lead to?

A
  • expansion of certain lineages

- increase of stem cell self-renewal

37
Q

what has very little proteomic analysis been done on stem cells?

A

proteomic analysis requires lots of cells and stem cells are rare

38
Q

when a HSC proteomic study was carried out on mice why was this so hard?

A

stem cells needed to be pooled from 600 mice

39
Q

what are the two types of mechanisms that control stem cells?

A

cell intrinsic and cell extrinsic

40
Q

what do signalling pathways do?

A

couple the extracellular environment to transcription and cell fate of stem cells

41
Q

name 5 different extracellular signals that are known to regulate stem cells

A
  1. cytokine
  2. growth factors
  3. hormones
  4. cell-cell junctions
  5. cell-matrix junctions
42
Q

give an example of three different signalling pathways that are found throughout development and in somatic tissues?

A

Wnt, Notch and Shh

43
Q

describe the signalling in mice epidermis and how this affects hair growth

A
  • Wnt signals for stem cells to proliferate
  • Notch signals for differentiation
  • Shh for proliferation
    and this results in hair growth
44
Q

describe the signalling in the intestine and how this affects cell fate

A
  • Wnt signals stem cells proliferations
  • Notch signals TA proliferations
  • Wnt and Notch signalling antagonise each other to determine where cells will become secretory or absorption
45
Q

name 4 different non-protein cell extrinsic factors that regulate stem cells and why are these becoming easier to study?

A
  1. ROS
  2. matrix stiffness
  3. environment shape
  4. pressure
    better technology is being developed
46
Q

give an example of how ROS regulate stem cells

A

elevated levels of ROS limit the lifespan of HSC by interfering with their quiescence

47
Q

give an example of how pressure regulates stem cells

A

specific genes expression is associated with the types pressure applied to MSC

  • dynamic tension regulates fibroblastic and oestogenic associated genes
  • compression up-regulates genes associated with cartilage

SCRA (19 decks)

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