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The nucleus, which is essentially the control system of the cell, is highly advanced and complex. It is composed of many different compartments, such as the lamina and pore complex-and these compartments play a large role in gene regulation and expression. This problem summary focuses on two of the nuclear compartments-euchromatin and heterochromatin. Euchromatin is gene-rich, decondensed chromatin and is the site of active transcription/gene expression. Heterochromatin, on the other hand, is gene-poor, heavily condensed chromatin and generally has minimal or no transcriptional activity (Fonseca-Carmo, 2002). Euchromatin and heterochromatin are thus the two states in which chromatin can be in. Genes move between the two compartments during cell development and differentiation. For instance, during erythroid differentiation, when the beta-globin gene is activated, it relocates away from the heterochromatin, where gene expression is low (Fonseca-Carmo, 2002). The focus of this problem summary is to investigate how these compartments are able to affect gene expression.
The position of chromatin in the nuclear periphery correlates with gene expression. Boyle et al. (2001) describes how most of the euchromatin is concentrated at the nucleus' center, and heterochromatin is at the nuclear periphery. Thus, the majority of active gene expression would occur in the center of the nucleus. To determine whether the correlation between location and gene expression has a causal link and to what extent gene location would directly affect gene expression, researchers conducted an experiment that involved tethering chromosomes (coiled chromatin) to the nuclear periphery, specifically onto the inner nuclear membrane proteins (Finlan et al., 2008). Upon tethering chromosomes with gene-rich regions directly to the nuclear periphery, they concluded that the gene expression of many, but not all, genes near the tethering site were significantly reduced. Also, some genes located further away from the tethering site, but still on the same chromosomes had their gene expression suppressed. The extent to which gene expression was altered, they proposed, may depend on the strength of the promoter (Finlan et al., 2008). Neighboring genes were largely unaffected. This shows that during cell development and differentiation, the function of genes locating to and from the nuclear periphery (or to and from heterochromatin) could be to regulate the expression of certain genes without changing the gene expression of neighboring ones (Finlan et al., 2008). The phenomenon, where gene expression is inhibited, is known as gene silencing, and this can occur when genes associate with heterochromatin at the nuclear periphery. However, a gene merely relocating towards the periphery to associate with heterochromatin does not fully explain how heterochromatin can silence genes.
Other factors, mainly from the nuclear periphery, need to be associated with heterochromatin in order to silence genes. The need to be in proximity with such factors may also explain why heterochromatin is located at the nuclear periphery. Researchers have found a region of histone hypoacetylation along the nuclear periphery that likely, in conjunction with genes situated in the periphery, facilitates the suppression of gene expression (Finlan et al., 2008). Deacetylation of core histones in heterochromatin around centromeres promotes silencing (Francastel, Schubeler, Martin & Groudine, 2000). In addition, proteins such as Ikaros, Sir-proteins, and methyl-DNA-binding proteins colonize with heterochromatin and mediate silencing (Francastel et al., 2000). Another study shows how silencers, such as cis-acting regulatory sequences, are required to maintain heterochromatic gene silencing (Chen & Gartenberg, 2000). Euchromatin, which is not associated with gene silencing, is located near high concentrations of RNA polymerase II and basal transcription factors-factors that promote active gene expression (Francastel et al., 2000). Thus, it is evident that certain factors that localize near and associate with chromatin help with chromatin's regulation of gene expression.
The structure of chromatin correlates with gene expression. Since euchromatin is loosely coiled and decondensed, it is made readily accessible to RNA polymerase II and basal transcription factors to instigate transcription. What determines the state of chromatin are the factors described above such as DNA-binding proteins and methylation, as these factors can alter the chromatin structure, which then correlates with a change in function (Francastel et al., 2000). Changing between the two forms of chromatin is in itself is a way to regulate gene expression as each form is associated with a level of transcriptional activity.
In reference to "Tweets from the Edge," Charlie 13, which is symbolic for chromosome 13, states how "being at the center of things isn't all that it's cracked up to be. It's so crowded." Charlie13 is thus at the center of heterochromatin which is heavily compact and is not ideal for gene expression. Chromosome 13 has genomic clusters (increased crowding) and a high percentage of misexpressed genes (Mewborn et al., 2010).
Conclusively, this problem summary has conveyed how chromatin can affect gene expression. Improper localization and organization of chromatin has implications on health issues. For instance, cancer is associated with disruptions in gene expression and with deviations in heterochromatin distribution within the nucleus. Mutations in genes associated with the organization of heterochromatin have shown to cause cancer (Prokocimer, Margalit & Gruenbaum, 2006). Future directives would thus be to understand and find ways in which chromatin organization can be controlled and ways to intervene in preventing disruptions in gene expression.
Boyle S., Gilchrist S., Bridger J. M., Mahy N. L., Ellis J. A., & Bickmore W. A. (2001).
The spatial organization of human chromosomes within the nuclei of normal and emerin-mutant cells. Human Molecular Genetics, 10(3), 211-219.
Boyle et al. conducted a study that showed a correlation between the density of genes in chromatin and location within the nucleus. They used techniques like FISH and used wild type and mutated cells to study the effects on preferential location.
Carmo-Fonseca, M. (2002). The contribution of nuclear compartmentalization to gene
regulation. Cell, 108(4), 513-521.
This review article provides a general overview of nuclear compartmentalization, and further describes the relationship between chromatin and gene expression.
Chen, T., Gartenberg, M. R. (2000). Yeast heterochromatin is a dynamic structure that
requires silencers continuously. Genes and Development, 14, 452-463.
This study looked at the role silencers had on heterochromatin and gene silencing at different stages of the cell cycle. They also showed how heterochromatin, though condensed, is a dynamic structure.
Finlan, L. E., Sproul, D., Thomson I., Boyle S., Kerr E., Perry P., â€¦ & Bickmore W. A.
(2008). Recruitment to the nuclear periphery can alter expression of gene in
human cells. PLoS Genetics, 4(3), 1-13.
After the discovery that the spatial organization of chromatin correlates with gene expression, this study further investigates whether organization actually affects or merely reflects gene expression.
Francastel, C., Schubeler, D., Martin, D. I. K., & Groudine, M. (2000). Nuclear
compartmentalization and gene activity. Nature Reviews Molecular Cell Biology, 1, 137-143.
This review article provided an overview of the other factors, namely histone deacetylation, that associate with heterochromatin by changing the structure of chromatin.
Mewborn, S. K., Puckelwartz, M. J., Megan J., Abuisneineh F., Fahrenbach, J. P., Zhang
Y., â€¦ & McNally, E. (2010). Altered chromosomal positioning, compaction, and gene expression with a lamin A/C gene mutation. PLoS ONE, 5(12), 1-13.
This study showed how gene expression was altered upon chromatin associating with the lamin in the nuclear periphery. They also showed how chromosome 13 has altered gene expressions.
Prokocimer, M., Margalit., A. & Gruenbaum, Y. (2006). The nuclear lamina and its
proposed roles in tumorigenesis: Projection on the hematologic malignancies and
future targeted therapy. Journal of Structural Biology, 115, 351-360.
This paper showed how chromatin organization and structure is critical for proper function; deviations can lead to health issues such as cancer.