Cell Differentiation

Question 1

What is cell differentiation?

Answer 1

The production of different cell types within an organism and this process is stable.

Question 2

How are cells or tissues that are used to damage and wear able to be maintained/replaced?

Answer 2

They are maintained by the differentiation of immature stem cells.

Question 3

What is determination?

Answer 3

The stability of cell differentiation even after the end of any inducing signal. It is transmitted to the daughter cells after division. E.g. different blood cells are all in the same enviroment, but they will ‘remember’ what cell type they are.

Question 4

What is cell lineage?

Answer 4

The series of cell types leading from the zygote to a particular cell type.
Differentiation in the embryo occurs in a series of steps from one immature or precursor cell type to another more mature cell (may still be some kind of precursor).

Question 5

How are skeletal muscles created?

Answer 5

Skeletal muscles comes from cells in the somite. Parts of the somite differentiates into the myotome which differentiate into a type of migrating cell, which migrates through the embryo to all the places where we want the skeletal muscle to be.

Question 6

What are myoblasts?

Answer 6

Myoblasts are precursors for muscle and when they get to the place they need to be, they start fusing together to start producing skeletal muscle.

Question 7

What does the suffix ‘-blast’ mean?

Answer 7

It means that the cell is a precursor cell type.

Question 8

Why do cell lineages often branch off?

Answer 8

The branches indicate that a particular kind of precursor cell is able to produce more than one kind of daughter cell given the right signals. For example there are several kinds of red and white blood cells from bone marrow stem cells during postnatal life.

Question 9

What are pluripotent stem cells?

Answer 9

A cell that is able to differentiate into all types of cells, an example of this is embryonic cells.

Question 10

How can cell types become different?

Answer 10

Different cell types express different sets of genes.

Question 11

What does gene expression mean?

Answer 11

The whole process leading to synthesis of the final product of a given gene; either a protein or a functional RNA like tRNA. Includes transcription and translation.

Question 12

Is a change in gene expression always differentiation?

Answer 12

No, there is also modulation.

Question 13

What is modulation?

Answer 13

• Gene expression is the synthesis of the product of a given gene – a protein or a functional RNAs like tRNA. It includes both transcription and (for proteins) translation.
• Differentiation involves an altered pattern of gene expression. But not all altered gene expression is differentiation. Cells can also undergo small, simple changes in gene expression in response to a specific stimulus, which are reversed when the stimulus is removed.
• This kind of change is called modulation (of gene expression).
• This is a transcriptional change that is reversible, and dependent on a continuing external stimulus. This can also be called adaptation.

Question 14

What is an example of modulation?

Answer 14

An example is the upregulation of alcohol dehydrogenase enzyme expression in hepatocytes (liver cells) in response to a rise in blood alcohol. The enzyme breaks down alcohol. So as the alcohol level falls again the enzyme switches off, not being made anymore

Question 15

What is the difference between differentiation and modulation?

Answer 15

-In comparison, both differentiation and modulation involve changes in gene expression but differentiation is a stable, complex change in gene expression, while modulation is a reversible (temporary), simple change.

Question 16

What are melanocytes?

Answer 16

They are pigment cells which can be used to study hw a cell differentiates.

Question 17

How are cell differences brought into by?

Answer 17

Through differential gene transcription.

Question 18

How can differential gene transcription be detected?

Answer 18

Using:

• individual ‘probes’- known DNA sequences, complementary to the sequence that you are looking for.
• By microarray or RNA sequencing- which can test for thousands of known RNA’s at once.

Question 19

What is activated during one step in lineage?

Answer 19

A diverse set of cell-type-specific genes is generally activated- some are repressed.

Question 20

What is a program of differentiation?

Answer 20

The new expression pattern- this is the set of genes that expressed in a given cell type. This program is largely controlled at the level of mRNA transcription.

Question 21

What do different cell types express?

Answer 21

-Different cell types express their own specialized gene products, although all or nearly all cells also express a basic set of necessary “household genes”, such as tubulin and histones.
-For example:
*Red blood cells express globin (the protein part of
haemoglobin)
*Skeletal muscle cells express specific actin and
myosin genes
*Skin fibroblasts make type I collagen
NOTE: These are just a few examples and each cell type actually has dozens of specific gene products. Some specialised gene products appear in several cell types rather than just one.

Question 22

How do we know that differential gene expression is not involved in the loss of genes?

Answer 22

All normal somatic (not germ-like) cells in our bodies have a complete set of chromosomes and genes – so differential gene expression does not generally involve losing genes.
We know this from “cloning” experiments, as with Dolly the Sheep (previously there were also many similar experiments with frogs and other organisms).
Here a whole differentiated adult cell (from epithelium of breast of other sheep) is fused to the cytoplasm of an oocyte from which the nucleus has been removed.
This makes the equivalent of a diploid zygote, but its nucleus comes from the adult cell.
Such a zygote sometimes develops successfully into a new complete animal.
This told us that a differentiated cell had all the genes needed to make all the cell types and that differentiation does not involve gene loss.
*There is one known exception in mammals where genetic material is lost, namely that when lymphocytes differentiate (or mature), small parts of their DNA are removed and lost to generate immunoglobulin diversity.

Question 23

How does chromatin remodelling work?

Answer 23

Chromatin remodelling is the way in which chromatin is arranged into one of its two alternative forms.
-Large stretches of chromatin can be tightly folded and
coiled into a condensed form that appears dark in
stained sections, heterochromatin (Folded – not in
use).
-Other stretches have a more open conformation that
looks paler on staining: euchromatin
-Transcription occurs predominantly in areas of
euchromatin. It seems that the protein machinery of
transcription is not able to get access to the DNA in
the highly-folded heterochromatic regions.
-Euchromatin into heterochromatin
-Affects a region of chromatin – can be several/many
genes or a whole chromosome.
-Different cell types have different sections of their
genome as heterochromatin.

Question 24

How does DNA methylation work?

Answer 24

-Occurs on the base cytosine within a CpG pair (=CG –
the p in between means phosphate and refers to the
fact that in between every 2 DNA bases there is a
phosphate) which means the opposite strand will also
have a CG pair. Cytosine is methylated to form
methylcytosine (modified base).
-Methylation of a gene (especially its promoter or
control sequence) has the effect of silencing
transcription which is developmentally regulated.
-Is copied to opposite strand (also CpG) by a
maintenance methyltransferase.
STEPS:
-When DNA replicates the Strands are separated (blue
strands with CH3 on them)
-The new complementary DNA is made, but at this point
the new strand is not methylated
-The maintenance methyltransferase enzymes goes
along all the DNA as its made looking for methyl
groups on the old strand and when it finds it, it adds
one on the new strand.
-This means that the pattern is remembered and copied
in the daughter cells in the same way the DNA itself is
copied.

Question 25

What is de novo methylation?

Answer 25

When DNA replicates the Strands are separated (blue strands with CH3 on them).
The new complementary DNA is made, but at this point the new strand is not methylated.
The maintenance methyltransferase enzymes goes along all the DNA as its made looking for methyl groups on the old strand and when it finds it, it adds one on the new strand.
This means that the pattern is remembered and copied in the daughter cells in the same way the DNA itself is copied.
CpG pairs are not always methylated. Unmethylated pairs can become methylated (during cell differentiation, including gamete formation – where a lot of the DNA is condensed down).
This is done by a de novo (new) methyltransferase (methylation – where it wasn’t there before).
STEPS:
-De novo methylation is instructed where to go by
certain binding factor and goes to methylates a certain
cytosine base.
-The maintenance methyltransferase finds it and
methylate’s the opposite strand
-Once you get the methylation it can be remembered
after that. However, under certain specific conditions it
can also be removed and then genes are
demethylated therefore become expressed.

Question 26

What does DNA methylation tend to occur in?

Answer 26

DNA methylation tends to occur in whole stretches, rich in CpG pairs. This methylated DNA becomes highly folded (heterochromatic). This is one important type of chromatin remodelling.

Question 27

How does specific transcriptional regulation work?

Answer 27

-This is done by a protein called the transcription
factors (which is a regulator of transcription), that bind
(via lock and key mechanism) to specific DNA
sequences in the gene’s promoter and alter the rate of
transcription (either increases or decreases it)
-The commonest place where they bind is the
promoter of genes which is a regulatory region of
DNA, 5’ (refer to sense strand) or “upstream” of the
start site for transcription of a gene.

Question 28

LOOK AT POSTER FOR THE STEPS INVOLVED IN SPECIFIC TRANSCRIPTIONAL REGULATION.

Answer 28

LOOK AT POSTER FOR THE STEPS INVOLVED IN SPECIFIC TRANSCRIPTIONAL REGULATION.

Question 29

What are master gene regulators?

Answer 29

-A kind of transcription factor
-Regulates transcription of a whole set of lineage-
specific genes (a “program”) for a given cell type.
-As a cell differentiates to its final functional state, its
specific genes are often activated by one or more
special transcription factors called master gene
regulators for that cell type.
-e.g. MyoD (Myogenic Differentiation) in skeletal
muscle – can activate a program of muscle-specific
genes, or Gata1 in erythrocytes.
-Expression or activation of these factors seems to be a
kind of master-switch that activates the whole set of
specific genes (sometimes called a differentiation
program) expressed by that cell type.
-In skeletal muscle this would include the genes for
muscle actin and myosin, muscle creatine kinase,
myoglobin, desmin, acetylcholine receptor and others.

Question 30

How does the mechanism for master gene regulator go?

Answer 30

-Gene for the master gene regulator is transcribed to
make proteins.
-Protein binds to the promoter in the different luxury
genes (ex: actin, myosin, creatine kinases)
-This activates transcription and thereby makes the
specialised proteins.

Question 31

What are the different 3 main division patterns that matured and differentiated cell types have?

Answer 31

-Cells may divide very little but can divide to repair damage (e.g. endothelium, liver).
-Cells that cannot divide - terminal differentiation. Some are not replaced when lost (e.g. neurons, lens).
-Terminally differentiated cells may be constantly replaced by division of precursor cells called postnatal stem cells (e.g. in bone marrow, gut epithelium, epidermis).
Where there is replacement from stem cells, there may be an intermediate precursor cell type or transit cell that is determined to the particular lineage yet still able to divide (Fig. 5), so that each differentiating cell coming from the stem cell can produce a large number of the final functional cells. (Transit cells: are committed cells in the process of dividing and differentiating).

Question 32

What are the abnormalities that can be caused by cell differentiation?

Answer 32

-Cancers do not generally appear to be caused by
defective differentiation, but differentiation is often
deficient in cancers, so many tumour cells resemble
precursors - “blast” cells or stem cells.
-E.g. neuroblastoma, retinoblastoma, glioblastoma, and
myeloblastic or lymphoblastic leukaemias
-Defects of differentiation are often lethal.
-But there are some (uncommon) non-lethal birth
defects where differentiation of a particular cell type is
affected. E.g.:
-Aniridia – lack of iris: due to mutation in transcription
factor PAX6.
-Congenital anaemia and thrombocytopenia (platelet
deficiency), due to mutation in transcription factor
GATA1, needed for differentiation of erythrocytes and
platelets.