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Regulation of Gene Expression > Ferrari: Lecture IX > Flashcards

Ferrari: Lecture IX Flashcards

miRNA: Regulation in Hematopoiesis

1
Q

Where does miRNA regulate and what characterizes its presence?

A

it is regulated in many different body systems and characterized by the presence of stem cells

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2
Q

What are the 4 model linages of stem and progenitor cells?

A

muscles
skin
nervous system
hematopoietic

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3
Q

Describe the muscle lineage differentiation

A

muscles contain muscle progenitors and differentiated cells

the main feature of the stem cells is the capacity of self-renewal

in this case the muscle progenitor is able to differentiate into different cells like satellite and myoblasts

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4
Q

Describe skin differentiation

A

embryo: embryonic epidermal skin cells

adult: epidermal skin cells which are responsible for skin renewal as we change them every 3-4 weeks and are localized in the derma

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5
Q

Describe nervous system differentiation

A

neuroepithelial stem cells give rise to differentiated cells

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6
Q

Describe hematopoietic differentiation

A

Hematopoietic stem cells are found in the peripheral blood and the bone marrow and give rise to rbc, wbc, etc.

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7
Q

What advantages for study do hematopoetic stem cells offer?

A

easier to isolate from bone marow (this is why HPSC are the most well studied and known)

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8
Q

What are some TF expressed only in the muscular system that regulate master genes?

A

MyoD
Myogenin
MYF5
PAX3
PAX7

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9
Q

Describe the hematopoietic hierarchy:

A

hematopoietic stem cells
↓
committed progenitors (not able to renew like HPSC) but they can differentiate in more than 1 lineage
↓
common myeloid progenitor (can give rise to both granulocytes and megakaryocytes and erythrocytes) so they are not lineage restricted, just committed
↓
common lymphoid progenitor (gives rise to B cells, T cells, and the NK compartment)

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10
Q

What characterizes the differential states of the hematopoietic hierarchy?

A

specific factors (cytokines and growth factors) and the expression of specific miRNA

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11
Q

Why are the factors that make the hematopoietic hierarchy important?

A

they allow for cell cultures to be synthesized and placed into specific lineages

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12
Q

How would we make a cell line to study erythropoiesis?

A

with stem cell factors IL3, and erythropoietin

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13
Q

How would we make a cell culture to study granulocytes?

A

with granulocyte stem factors IL3, IL6, and so on

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14
Q

When and who discovered the hematopoiesis was organized in a cellular hierarchy?

A

Maximow in the 19th century

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15
Q

Why was the organization of hematopoiesis important?

A

it was sustained by the consequences of the atomic war

survivors had cancers and neoplasia of the lymhoid/hematopoietic system, so they needed transplants from donors

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16
Q

Stem Cells

A

self-renew, generate daughter stem cells, and can contibute to a pool of differentiated stem cells

these features CANNOT be found in progenitors and in differentiated cells

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17
Q

How were HPSC found and defined?

A

TIll and McCulloch performed a clonal in-vivo repopulating assay in a mouse in 1961

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18
Q

The pool of hematopoietic stem cells, progenitors, or the differentiated cells express different _______

A

surface markers

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19
Q

Why is it important to note that hematopoietic stem cells, progenitors, or the differentiated cells express different surface markers?

A

we can use antibodies to have cell sorting

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20
Q

What are the 2 essential factors that induce the proliferation of differentiation of stem cells in vivo?

A

intrinsic factors and extrinsic factors

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21
Q

Give examples of intrinsic factors

A

TF
miRNA

22
Q

Give examples of extrinsic factors

A

cytokines
networks

23
Q

Where are HPSC located in embryo?

A

fetal liver

24
Q

Where are HPSC located in adults?

A

bone marrow

25
Q

What is the microenvironment of the bone marrow?

A

bone marrow niche

26
Q

Why are the cells that pertain to the stromal component, the vascular component, and the osteoblastic component of the bone marrow important?

A

they are the ones able to release factors and do cell-cell interactions

27
Q

What is required for the formation and function of hematopoietic stem cells?

A

critical transcription factors

28
Q

What defines the stem cells?

A

miRNAs

29
Q

How are HPSC from the primitive compartment isolated?

A

bone marrow cells fro mouse are extracted using a syringe → surface markers of primitive compartment are exploited using antibodies → cells are sorted using flow cytometry

30
Q

What was a result that was being sought out in this paper in regards to HPSC?

A

isolate the HPSC-specific miRNAs

31
Q

Gain of Function Approach

A

expression of a gene is induced at a supraphysiological level to see the effects of overexpression

32
Q

Loss of Function

A

abrogate the expression of a gene

33
Q

Why are vectors derived from viruses used?

A

because a virus’ job is to transfer their genome into the host cell and using the machinery for their cell cycle

34
Q

What are the most powerful viral systems?

A

vector derived from Mo-MLV: retrovirus (Moloney leukemia virus that infects mice, carries oncogenes, and causes leukemia)

vector derived from HIV-1: human virus (Lentivirus class of the retroviral family)

*the genome for both is RNA

35
Q

Mo-MLV

A

small piece of RNA

at the ends of the terminal are located long terminal repeats, where the strong promoter is located

fundamental genes (form the viral particles) code for: capsid proteins, reverse transcriptase, envelope proteins

36
Q

What are the 2 type of elements that make HIV complex?

A

cis-acting and trans-acting elements

37
Q

trans-acting elements

A

sequences required for the formation of the viral particle:
gag
pol
env

38
Q

cis-acting sequences

A

required for the assembly of the viral genome into the viral particles:
PBS (primer binding site)
DIS (genome dimerization signal)
Ѱ (packaging signal)
PPT (polypurine track, downstream env)
polyA (poly adenylation sequence, in R)
U & R (unique and redundant sequence)
SD & SA (splice donor and acceptor , scattered)

39
Q

Which one of the cis-acting sequences is of particular importance?

A

Ѱ signal: in the RNA genome and allows this genome to be included in the viral particle

40
Q

What happens if you use technology to remove almost all of the genes of a virus and only keep the LTR and Ѱ signal?

A

the retroviral vector is cloned and the expression of the construct of interest (gene, miRNA, protein coding gene) will be driven by the strong viral promoter

41
Q

What does it mean if miRNA are expressed at a lower level?

A

no leukemia

42
Q

What does it mean if the same miRNA is expressed at a high level?

A

leukemia

43
Q

Why is the field of miRNA in literature full of paper regarding cancer?

A

the expression of specific miRNAs are completely dysregulated in cancers, so much so that they are almost markers for neoplastic growth, useful for diagnosis and prediction

44
Q

What are the 3 sources of HPSC in humans?

A

cord blood
bone marrow
peripheral blood

45
Q

What is a surface marker for stem cells in humans in cord blood, peripheral blood, and bone marrow?

A

CD34 (this is the marker used for transplantation)

46
Q

What happens after CD34 is extracted from the core blood for a transplant?

A

qPCR is performed (not microarray because the mouse model shows us miRNAs are present) after the miRNA has been designed

47
Q

What is a human mouse chimera?

A

mouse that can accept transplantation of human cells and can have human blood circulating

48
Q

How can a mouse have human blood circulating?

A

it is immunodeficient in B, T, and NK murine cells

*they are extremely immunodeficient

49
Q

If miR-125b1 is added to immunodeficient mice, what occurs?

A

human cells demonstrate the expression of this miRNA and enable better engraftment, homing, and differentiation

*it is also observed in humans

50
Q

there is an evolutionary conserved subset of miRNAs, which are particularly important in terms of expression in the __________

A

hematopoietic primitive compartment

51
Q

miRNAs in the hematopoietic primitive compartment must be _____ because _____ means cancer

A

tightly regulated

dysregulation

Regulation of Gene Expression (28 decks)

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