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Within the process of cellular differentiation, cells acquire specific phenotypes that suit their unique functions. A differentiated cell has some of its genes activated, whereas the remaining genes are silent (Freeman, 2005). This shows that cells have the ability to regulate their gene expression. The expression of genes can be regulated at various levels: transcriptional level, translational level, and post-translational level. In eukaryotic cells, DNA is tightly associated with proteins which create protein-DNA complexes known as chromatins (Freeman, 2005). Chromatins are dynamic structures, which can reposition themselves within the nuclear space (Lanctot, Cheutin, Cremer, Cavalli, & Cremer, 2007). Before transcription can begin, RNA polymerase and other required factors must be able to reach the loci that need to be expressed, which means that the DNA sequences should be released from the tight interactions with proteins. The decondensation process of chromatins before transcription is referred to as chromatin remodeling (Freeman, 2005). Increasing evidence demonstrates that the position of chromatins within the nucleus, their dynamic interactions with nuclear compartments, and topological organization of the nucleus affect how gene expression is regulated in eukaryotic cells (Francastel, Schubeler, Martin, & Groudine, 2000). In this paper, the effects of nuclear compartmentalization on the regulation of gene expression are investigated by looking at the functions of chromosome territories. The remainder of this paper is organized by first explaining chromosome territories and their functions. Then, by using information extracted from literature, the functions of chromosome territories are supported. Lastly, the medical implications for studying chromosome territories are discussed.
The discrete individual region that each chromosome occupies in the nuclear space during interphase is known as a chromosome territory (Bode, Goetze, heng, Krawetz, & Behnam, 2003). Chromosome territories divide the nuclear space into transcriptionally active and inactive regions, wherein each region is associated with their respective activation or repression factors (Francastel et al., 2000). Therefore, these structures and the spatial organization that they create for the genome are thought to be involved in gene regulation and genome stability (Meaburn & Misteli, 2007). Using fluorescent tags, chromosome territories can be visualized in vivo as spherical domains with a diameter of about 2 micrometer (Meaburn & Misteli, 2007). The interiors of chromosome territories are filled by highly interconnected branched networks of channels which make these regions accessible to different regulatory factors (Cremer & Cremer, 2001). The genes are also compartmentalized within a chromosome territory. These compartmentalizations allow potentially active genes to be close to the boundary of the territory and non-coding sequences and inactive genes to be close to the center of the chromosome. This organization makes it possible for transcriptional factors to make contact with genes that need to be expressed (Meaburn & Misteli, 2007). However, the mechanism which leads to gene organization within a chromosome territory is not well understood (Cremer & Cremer, 2001). In general, chromosome territories are arranged in particular patterns, wherein each chromosome is located in a preferential position toward the nuclear center and other chromosomes. These patterns are shared between the cells that belong to the same tissue type or cells that share a common developmental pathway. In fact, this shows that there is a correlation between the differentiation process and chromosome positioning. For example, during the differentiation process of immune T cells of mice, chromosome 6 moves from the center of nucleus toward the peripheral area (Meaburn & Misteli, 2007). Nonrandom distribution of the genome through chromosome territories not only leads to compartmentalization of the nucleus to transcriptionally active and inactive regions, but also results in the coordination of the activities of co-regulated genes or in other words functional compartmentalization. For instance, the genes that encode rRNA are clustered in a nuclear organelle called nucleolus (Meaburn & Misteli, 2007).
There are two mechanisms suggested to explain how chromosomes position themselves within the nuclear space. In the first mechanism, the nuclear matrix which is essentially a network of fibers attaches to chromosomes and anchors them to their location (Bode et al., 2003). This mechanism is able to explain the stability and immobility of chromosomes, however it does not explain the their nonrandom distribution. The second mechanism relates the position of each chromosome to the activity of its genes and purposes a self-organizing system for the genome organization. The idea here is that the active genes are decondensed and inactive genes are condensed, and as a result chromosomes are composed of regions with different degree of condensation. Therefore each chromosome has a unique physical characteristics based on its gene activity and that is how is positions itself relative to other chromosomes (Meaburn & Misteli, 2007).
Studying chromosome territories can lead to a better understanding of the mechanisms involved in gene expression regulation in eukaryotes. The knowledge gained can also be used for clinical applications in near future. For instance, any changes in the organization of genome within the nucleus can be considered as an indicative of a disease process. In addition, as positional changes of chromosomes are initial steps of genetic variation, positional analysis can be used as an early diagnosis of diseases. The advantage of positional analysis is that it can be used to detect abnormal cells within intact tissue without the need for cell culturing (Meaburn & Misteli, 2007).
Bode, J., Goetze, S., heng, H., Krawetz, S.A., & Behnam, C. (2003). From DNA structure to gene expression: mediators of nuclear compartmentalization and dynamics. Chromosome Research, 11, 435-445.
This study demonstrates that eukaryotic genomes are functionally compartmentalized into chromatin domains by their attachment to the nuclear matrix, where these attachment are dynamic. Therefore cells can modulate their gene expression by changing the contacts between the matrix and the genome.
Cremer, T., & Cremer, C. (2001). Chromosome territories, nuclear architecture and gene regulation in mammalian cells. Nature , 2(April 2001), 292-301.
This study focusses on gene regulation mechanisms that take place by the interaction between chromosome territories and other nuclear compartments. This work purposes that the location of a gene within the chromosome territory influences its transcription.
Francastel, C., Schubeler, D., Martin, D.I.K., & Groudine, M. (2000). Nuclear compartmentalization and gene activation. Molecular cell Biology, 1(November 2000), 137-143.
This study indicates that gene regulation is influenced by nuclear organization, where the specific expression pattern of each eukaryotic cell is determined by the regions of the genome that are accessible to the transcriptional apparatus.
Freeman, S. (2005). Biological science. New York: Pearson.
This book is a general biology book, which provides fundamental knowledge about most of the biology topics.
Lanctot, C., Cheutin, T., Cremer, M., Cavalli, G., & Cremer, T. (2007). Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nature , 8(February 2007), 104-115.
The subject of this study is to determine how the interactions between DNA and regulatory factors are influenced by when and where these interactions take place. This study suggests that activating or silencing a gene is associated with repositioning of the locus relative to other nuclear compartments.
Meaburn, K.J., & Misteli, T. (2007). Chromosome territories - news & views. Nature , 445(27 January 2007), 379-381.
This article describes the knowledge available about chromosome territories in the form of questions and answers. This review presents the current view of this nuclear compartment and predicts how this topic may be useful in medicine in future.
This assignment could be considered as a reflective practice, because while I was working on it, I had to read through literature, interrupt the information, examine their relevancy to the topic, and extract the portion that could be used for this work. The active process of thinking and interpreting around the inquiry made this assignment a reflective practice.
The objective of this exercise was to determine the role of nuclear compartmentalization in gene expression. I had to choose one of the nuclear compartments and inquire its function for gene regulation. There were a couple of challenges that I encounter. The first challenge was to choose a compartment which could be investigated in the context of gene regulation. Therefore I spent some time to look at the functions of all the compartments in the nucleus. The second challenge is that there are many relevant studies available, which differ in how they view the topic. As a result, I had to seek deeper into literature to present the most valid information in my paper. I believe I have tried to address the objectives of the assignment based on the guideline provided for it. In other words, I tried to first introduce some basic knowledge about gene regulation in eukaryotic cells and then pose the general question in my introduction. Then I defined the chosen compartment (chromosome territories) and discussed its role in gene regulation. Lastly I addressed the clinical implication that this topic may have in future. Next time, I can work more on my English and I can provide more experimental results to support my arguments.