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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: ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 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. 65 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. ________________________________ ________________________________ ________________________________ 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. ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 66 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. ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 67 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. ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 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. ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 68 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. ________________________________ ________________________________ ________________________________ 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 ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ ________________________________ 69 STUDENT RESPONSES What is the purpose of differentiation, and why do cancer cells typically not form from highly differentiated cells? _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ ____________________________________________________________________________________________________ Remember to identify your sources _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ _____________________________________________________________________________________________________ Wo r k b o o k Lesson 2.4 _____________________________________________________________________________________________________ ___________________________________________________________________________________________ 70 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. 71