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LESSON 2.4 WORKBOOK
How does a cell specialize?
DEFINITIONS OF TERMS
Cell differentiation – the process of cellular specialization.
Stem cells – a type of cell that
can differentiate into many different cell types.
Embryonic stem (ES) cells –
cells from an early stage in human development that can form
any type of cell in the body.
Self-renewal – the ability of a
cell to replicate itself identically
through mitosis.
Lineage – cells that originate
from one stem cell and constitute
a particular tissue type. The
pathway to forming a lineage has
multiple steps.
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.4
Every cell in our body contains more or less the same DNA, yet cells look different
and performs very different functions. This ability to specialize is possible because
not every cell uses its DNA in the same way – cells are different because they use
make different proteins. This lesson will examine how cells regulate which genes are
transcribed into proteins.
Cell differentiation: generating lineages
When a sperm and egg cell fuse to form a single fertilized cell, that one cell holds all the genetic information needed to make a complete person. However, once that one cell has divided to make an entire
person, we find that the cells in our body are not identical, which is why we can’t see with our tongue, or
digest with our feet, or think with our ribs. In order to get from a single cell to a human being two things
must happen: First, the original cell must divide so that there are enough cells to constitute the human
body. Second, at the same time the egg is turning into an embryo and then into a child and then an adult
the cells must specialize to make tongues, feet and ribs for example.
This specialization of cell function is called cell differentiation. In the beginning the undifferentiated egg
divides into a small population of cells that are identical. Each of these cells has the potential to form all
the cells in the body, so they are called stem cells. Because they are made as the fertilized egg is turning
into an embryo they are called embryonic stem cells (ES cells). When an embryonic stem cell divides by
mitosis the siblings it generates are not identical. Instead one sibling looks just like the original ES cell – this
is called self-renewal. The other sibling will enter a cell lineage. A cell lineage is like a family tree that
maps the steps a stem cell takes to turn into a fully specialized cell. There are a number of different cell
lineages – bone cells, muscle cells, nerve cells for example. Most cell lineages require several generations
before a stem cell becomes fully differentiated.
Eventually the body matures and by that time most, but not all cells in a particular lineage will have
completely differentiated. The final stage of differentiation is called terminal differentiation. However
some cells in a lineage will stay immature (these are called progenitor cells). The immature progenitors play an important role if a tissue is damaged: Many terminally differentiated cells, lose the ability to
MC Questions:
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1. Which of the following are properties
of an embryonic stem cell? (Circle all
correct.)
aa. It can self-renew.
bb. It can make blood cells.
cc. It can only make blood cells.
dd. It is only found in the embryo.
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LESSON READINGS
DEFINITIONS OF TERMS
Terminal differentiation – the
final stage of cell specialization in
which a cell acquires the ability to
perform its mature function.
Progenitor cell – a cell that is
more differentiated than a stem
cell but that still has not terminally
differentiated and may be able
to differentiate into a number of
different cell types.
Adult stem cells – Cells able
to differentiate into different cell
types that are found in mature
tissue.
Express a protein – to make a
protein from DNA.
Wo r k b o o k
Lesson 2.4
divide – neurons and muscle cells are
important examples. But cells must
divide when a tissue needs repair.
Immature progenitors of a cell lineage
that still have the ability to divide are
able to respond to damage when fully
mature members of the lineage cannot.
The adult organism also contains very
immature cells that are more like stem
cells than progenitors because they
can develop into more than one cell
lineage. They are called adult stem
cells, because they are found in adults
not embryos.
MC Questions:
2. Which of the following are behaviors
of progenitor cells? (Circle all
correct.)
aa. Differentiation.
bb. Fertilization.
cc. Loss of the ability to divide.
dd. Self-renewal.
Figure 1: Stem cells can either self-renew
indefinitely or choose to specialize. Specialization
often occurs in multiple steps.
The process of cell differentiation is a
process of ongoing specialization. For
example, just like an elementary school graduate could (in principle) pursue any type of career, so an
ES cell can differentiate into multiple lineages. However as the student begins to specialize their career
options become more limited. A college graduate with a bachelor’s degree in chemistry has chosen a
more limited set of fields that they can work in (like an adult stem cell). If they have a Master’s degree in
physical chemistry those career options are limited even further (like a progenitor cell). Finally a Ph.D. in
molecular spectroscopy is even more specialized (like a terminally differentiated cell).
Regulating cell differentiation: protein expression.
How can some cells retain the ability to divide, while other cells lose that ability? Why are neurons different from blood cells? The differences between cells lie not in their genomic DNA, which is to all intents
and purposes identical between different cells, but in how that DNA is used to make proteins: If a cell not
longer makes Cyclin proteins, it won’t be able to divide; If a cell makes hemoglobin it will be a blood cell.
How a cell behaves depends on the proteins it makes (the term is to express a protein) because proteins
underlie both cell structure and cell function. To briefly review, DNA is divided into genes, each gene
codes for a protein. To express a protein DNA is first transcribed into RNA, then RNA is translated into
protein.
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3. Which of the following cells can
differentiate into the most cell types?
aa. Adult stem cell.
bb. Embryonic stem cell.
cc. Progenitor cell.
dd. Terminally differentiated cell.
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LESSON READINGS
The first step of gene transcription is key and requires two things to happen:
1. The DNA must be available for transcription
2. A transcription factor or factors must bind to the gene’s DNA and permit transcription to occur.
DNA folding determines whether genes are available to be transcribed
DEFINITIONS OF TERMS
If our DNA was loosely wound and all the chromosomes
placed end-to-end, our genomic DNA would be about 2
meters in length! Since an average nucleus is less than
a millionth of a millimeter this clearly doesn’t happen.
Instead DNA in the nucleus is carefully folded around
proteins in the nucleus called histones. Because
histones are positively charged and DNA is negatively
charged the DNA can be packed very tightly. When DNA
is packed tightly like this genes cannot be transcribed
because the RNA polymerase that transcribes the DNA
into RNA cannot get access. Only DNA that is loosely
attached to histones is accessible to RNA polymerase.
Histones – positively charged
proteins that bind DNA and help
to pack DNA in the nucleus.
Acetyl groups – a negatively
charged group with the formula
CH3COO– that when added to
histones neutralizes their positive
charge and prevents them
binding to DNA.
Methyl groups – a positively
charged group with the formula
CH3 that can be added to
histones or DNA. When added to
histones it increases the positive
charge and when added to
DNA it decreases the negative
charge. In both cases this causes
histones and DNA to bind more
tightly to each other.
Epigenetics – the study of how
modifications to the DNA that
do not affect DNA sequence
affect the phenotype of a cell or
organism.
Wo r k b o o k
Lesson 2.4
The first step in ensuring that different types of cells
express the different proteins they need to perform their
specialized functions is to ensure that genes needing to
be expressed have loosely wound DNA, while genes not
needing to be expressed have their DNA packed away
and inaccessible. DNA can be unwound from histones
by adding small chemical groups to histones that are
negatively charged. For example acetyl groups are small
molecules with chemical formula CH3COO–. The negative charge on the acetyl group to decreases the overall
positive charge of histones, and loosens their grip on DNA, allowing RNA polymerase to gain access.
Figure 2: DNA is negatively
charged and histones are positively
charged. When DNA is bound to
histones it will be tightly packed
and inaccessible to RAN polymerase. Modifications that reduce
histone binding open up DNA for
transcription.
Conversely, removing any acetyl groups, or adding chemical groups with positive charges such as
methyl groups with the chemical formula of CH3, will keep histones positively charged giving them a
tighter grip on the negative charges of DNA. DNA can be packed up even more by adding methyl groups
to the DNA itself, reducing its negative charge. The study of how histones and DNA can be modified to
increase or decrease gene expression is called epigenetics, and is currently a growing area in cancer
research.
MC Questions:
4. What is the difference between a
stem cell and an intestinal epithelial
cell? (Circle all correct.)
aa. Only stem cells produce proteins
that regulate cell division.
bb. Only intestinal epithelial cells
produce proteins that regulate
nutrient transport.
cc. Only stem cells can still divide.
dd. Epithelial cells can produce
many different types of cells.
5. Which of the following is a way to
decrease gene expression? (Circle
all correct.)
aa. Adding acetyl groups to
histones.
bb. Adding methyl groups to
histones.
cc. Adding methyl groups to DNA.
dd. Removing methyl groups from
DNA.
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LESSON READINGS
DEFINITIONS OF TERMS
Transcription factors – proteins
that are responsible for promoting
the expression of certain genes.
Transcription factors determine which genes are expressed
MC Questions:
Genes are transcribed by RNA polymerase, which binds to the gene and moves along it, reading the
gene’s DNA sequence and translating it into RNA. But RNA polymerase needs a guide that tells it where
a gene begins and therefore where it should start transcription. Every gene has a small region in front
of the DNA that will code for RNA and eventually protein called the promoter sequence. The promoter
sequence acts as a target for proteins called transcription factors. When a transcription factor is bound
to the promoter sequence, RNA polymerase knows that it should start transcribing that gene into RNA.
Each gene has transcription factors that bind to its promoter sequence. Some of these are specific to a
certain gene, while some transcription factors are shared across gene families.
6. How do transcription factors regulate
gene expression? (Circle all correct.)
aa. By binding specific DNA
sequences.
bb. By copying DNA to make RNA.
cc. By converting RNA to protein.
dd. By indicating to RNA polymerase
that it should bind to a gene.
Cells can use transcription factors to
determine which proteins are expressed.
For instance some transcription factors
present in epithelial stem cells will be
different from terminally differentiated
epithelial cells and the transcription
factors found in terminally differentiated
epithelial cells will be different from those
found in terminally differentiated bone
Figure 3: A gene can only be transcribed when
cells. However, not all gene expression
transcription factors bind to the promoter
sequence at the start of the gene DNA, guiding the
is completely different between different
RNA polymerase into place.
types of cells since all cells have
structures and functions in common –
many components of cell membranes
are identical in different cells for example, and most cells metabolize similarly.
Regulating cell differentiation: cancer.
Wo r k b o o k
Lesson 2.4
Many terminally differentiated cells can no longer divide. This has advantages for tissues like neurons
that are part of an elaborate network. If neurons could continually divide it would be difficult to maintain
such a complex structure like the brain that depends on trillions of precise connections between billions
of neurons. When terminally differentiated neurons that cannot divide are damaged they either die or
cease to function, they do not divide. Hence they have no opportunity to acquire the kind of mutations
that would turn them into hyperproliferating tumors. Because of this there are few if any tumors of mature
neurons. Tumors that appear in the brain are either from the supporting tissues of the stroma or from
primitive progenitor cells that are kept around precisely so they can provide substitutes when neurons are
damaged.
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7. How do transcription factors control
differentiation of the cell?
aa. Changing the expression of
proteins in the cell.
bb. Changing the membrane
potential of the cell.
cc. Changing the folding of DNA.
dd. Changing the lineages of the
cell.
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LESSON READINGS
Not all terminally differentiated cells have lost the ability to divide. Epithelial cells are good examples. As
we learned in lesson 2.1, epithelia are constantly exposed to the environment and therefore extremely
vulnerable to damage so epithelial tissue needs to be constantly prepared to repair damage. Because of
this they have ample opportunity to acquire tumor-causing mutations, and indeed, as we have seen, the
majority of cancers arise from epithelial cells.
DEFINITIONS OF TERMS
Tumorigenic – an event that
causes a tumor to form.
Many tissue types, especially those whose terminally
differentiated cells have lost the ability to divide, keep a
store of progenitors that they use to replace terminally
differentiated cells if they are damaged. These progenitors are less vulnerable to acquiring mutations than we
might imagine because they don’t divide continuously,
only when they receive a signal to do so. In this regard
however, one of those signals comes from inflammation, so people suffering from continual low levels of
inflammation are vulnerable. Another reason some
tissues maintain a store of progenitors is to replace
cells that have a short life span – blood and immune
cells are examples of this. These cells are continuously
dividing and so they are vulnerable to acquiring tumorigenic mutations, and indeed cancers of the blood are
common.
8. Which kinds of cells are least
vulnerable to tumorigenic
mutations?
aa. Stem cella;
bb. Epithelial cells;
cc. Neurons; or
dd. White blood cells.
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Figure 4: Germ cells are cells
in our body that can differentiate
into any cell type. This is why some
germ cell tumors form teeth!
Finally the most primitive cells in the body are the germ cells (eggs and sperm) because they fuse to form
an embryonic stem cell that can make all body components. Tumors of germ cells are quite common and
interestingly often contain many different tissue types. Fortunately most germ cell tumors are benign.
Wo r k b o o k
Lesson 2.4
MC Questions:
9. True or False: tumors are common in
all types of cells
aa. True
bb. False
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STUDENT RESPONSES
What is the purpose of differentiation, and why do cancer cells typically not form from highly differentiated cells?
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Wo r k b o o k
Lesson 2.4
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TERMS
TERM
For a complete list of defined
terms, see the Glossary.
Wo r k b o o k
Lesson 2.4
DEFINITION
Acetyl groups
The molecule CH3COO– that can be added to histones to put DNA in an “open” form and promote gene
expression.
Adult stem cells
Unspecialized cells that form a number of different (but not all) cell types in the body.
Dedifferentiation
The process where cell specialization is lost in favor of general cell behavior, like growth.
Differentiation
The process of cellular specialization.
Epigenetics
The study of how modifications to the DNA that do not affect DNA sequence affect the phenotype of a cell
or organism.
Germ cell
A cell that gives rise to sperm or egg cells which has high potency.
Histones
Positively charged proteins that bind DNA and help to pack DNA in the nucleus.
Lineage
The group of cells that are related that originated from one specialized cell in human development.
Methyl groups
The molecule CH3 that can be added to histones or DNA to pack DNA more tightly and inhibit gene
expression.
Embryonic stem (ES)
cells
Cells from an early stage in human development that can form any type of cell in the body.
Potency
The ability of a cell to differentiate into various cell types.
Progenitor cell
A cell that is more differentiated than a stem cell but still able to differentiate into a number of different cell
types, but cannot undergo self-renewal.
Self-renewal
The ability of a cell to replicate itself identically through mitosis.
Terminally differentiated
cell
A cell that is differentiated to the highest level, so that it performs a specific function in the cell, and is not
able to replicate.
Transcription factors
Proteins that are responsible for promoting the expression of certain genes.
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