Transcription Factory

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A transcription factory during transcription. Here the possibility of transcribing more than one gene at a time is highlighted. The diagram shows 8 RNA polymerases, the number of which can vary depending on the cell type.

In genetics , transcription factories (also known as transcription foci) describe the locations where transcription takes place in the cell nucleus . They were first discovered in 1993 and have structures similar to replication factories, i.e. places where replication takes place. The transcription factories contain an RNA polymerase (active or inactive) and the necessary transcription factors ( activators and repressors ) for transcription. Transcription factories containing RNA polymerase II have been studied most intensively to date. There may also be factories for RNA polymerase I and III; the nucleolus can be seen as a prototype for transcription factories. It is possible to view them under both light and electron microscopy . The discovery of the transcription factories has challenged the original view of how RNA polymerase interacts with DNA . It is believed that the presence of these factories has important effects on gene regulation and the structure of the cell nucleus.

discovery

The first use of the term "transcription factories" was in 1993 by DA Jackson and colleagues, who found that transcription occurred at specific points in the core. This contradicted the original view that transcription was evenly distributed across the nucleus.

structure

The structure of a transcription factory seems to be determined by the cell type, the transcription activity of the cell, but also by the method used by technology to visualize the structure. A generalized view of a transcription factory would contain between 4 and 30 RNA polymerase molecules. It is believed that the more transcriptionally active a cell, the more polymerases there are in a factory to meet transcription requirements. The core of a transcription factory is porous and protein-rich, with the hyperphosphorylated, elongated polymerases on the edge. Proteins present include: ribonucleoproteins , coactivators , transcription factors , RNA helicase, and splicing and processing enzymes. A factory contains only one type of RNA polymerase. The diameter of the factory varies depending on the RNA polymerase used; the RNA polymerase I factories are about 500 nm wide, while the RNA polymerase II and III factories are an order of magnitude smaller at 50 nm. It has been shown experimentally that a transcription factory is stationary. It is postulated that this immobilization is due to binding to the core matrix . Here it has been shown to be bound to a structure that is unaffected by restriction enzymes. Proteins believed to be involved in binding include spectrin , actin, and lamin .

function

The structure of a transcription factory is directly related to its function. The transcription is made more efficient by the bundling nature of the transcription factory. All the necessary proteins such as RNA polymerase, transcription factors and other co-regulators are present in the transcription factory, which allows for faster RNA polymerisation when the DNA reaches the factory. It also enables a number of genes to be transcribed at the same time.

number

The number of transcription factories present per nucleus appears to be determined by the cell type, species and the type of measurement. Embryonic fibroblasts from breeding mice were found to contain approximately 1500 factories as detected by immunofluorescent detection of RNA polymerase II. However, cells from different tissues from the same group of mice had between 100 and 300 factories. Measurements of the number of transcription factories in HeLa cells gave different results. For example, 300–500 factories were found using the traditional fluorescence microscopy approach, but around 2,100 were detected using confocal and electron microscopy.

Specialization of factories

In addition to the specialization of factories through the type of RNA polymerases they contain, they can have a further level of specialization. There are some factories that only transcribe a specific set of related genes. This further strengthens the concept that the main function of a transcription factory is transcription efficiency.

Assembly and maintenance

It is debated whether transcription factories merge due to the transcriptional requirements of the genome or whether these are stable structures that persist over time. Experimentally, it appears that they remain fixed for a short period of time; newly produced mRNA were labeled for 15 minutes and no new transcription factories were found. This is also supported by experiments to inhibit transcription. In these studies, a heat shock was used to turn off transcription. This did not result in any change in the number of polymerases recorded. Upon further analysis of the Western blot data, it was believed that there was indeed a slight decrease in the number of transcription factories over time. Hence, one could argue that the polymerase molecules are released from the factory over time when there is a lack of transcription. This would ultimately lead to the complete loss of the transcription factory.

There are also several indications that transcription factories are being rebuilt due to transcription needs. Fluorescence experiments with GFP polymerase have shown that the induction of transcription in the polytene chromosomes of Drosophila leads to the creation of a factory. This contradicts the notion of a stable and secure structure.

Mechanisms

The hypothesis presented here is that it is the transcription factory that remains immobilized during transcription and not the DNA template. It shows how a section of the gene to be transcribed (brown) is pulled during the process and passed through the RNA polymerase.

Previously it was assumed that it was the relatively small RNA polymerase that moved along the comparatively larger DNA template during transcription. However, increasing evidence suggests that because a transcription factory is attached to the nuclear matrix, it is actually the large DNA molecule that is moved to take up RNA polymerization. For example, in vitro studies have shown that RNA polymerases bound to a surface are able to both rotate the DNA template and pass it through the polymerase to start transcription; this shows that RNA polymerase is a molecular motor. Investigations with the chromosome conformation capture (3C) technique also support the idea that the DNA template diffuses through a stationary RNA polymerase.

However, there are also doubts about this proposed mechanism of transcription. First, it is not known how a stationary polymerase is able to transcribe genes on the (+) strand and (-) strand at the same genomic location at the same time. In addition, there is a lack of conclusive evidence of how the polymerase remains immobilized and what structure it is bound to.

Influence on the genomic and nuclear structure

The binding of related genes to the RNA polymerase and the necessary transcription factors cause the formation of a chromatin loop, which influences the structure of the genome.

The formation of a transcription factory has several consequences for nuclear and genomic structures. It has been suggested that the factories are responsible for the nuclear organization. It has also been suggested that two possible mechanisms promote the formation of chromatin loops:

The first mechanism suggests that loops form because two genes on the same chromosome require the same transcription engine, which would be found in a particular transcription factory. This requirement pulls the gene locations into the factory, creating a loop.

The second mechanism suggests that the formation of a chromatin loop is due to "entropic attraction" (English. Depletion attraction). This is a physical phenomenon that occurs when a relatively large object (e.g. a transcription factory) is in an area filled with soluble objects (e.g. proteins). The transcription factories tend to aggregate. This aggregation prevents smaller objects from becoming part of the overlap region. This reduces the entropy of the system. Therefore, a chromatin loop would form between the two factories.

Transcription factories are also suggested to be responsible for gene clustering as related genes would require the same transcription engine. If a factory met these requirements, the genes would be attracted to the factory.

While grouping genes can be beneficial for transcription efficiency, it could also have negative consequences. Gene shifts occur when the genes are in close proximity to one another; they are more common when a transcription factory is in place. Gene translocation events, such as point mutations , are usually harmful to the organism and can therefore lead to diseases. On the other hand, however, recent research has shown that there is no relationship between interactions between genes and the frequency of translocations.

See also

Individual evidence

  1. ^ Iborra F: Active RNA polymerases are localized within discrete transcription "factories" in human nuclei . In: Journal of Cell Science . tape 109 , 1996, pp. 1427-1436 .
  2. ^ DA Jackson, AB Hassan, RJ Errington, PR Cook: Visualization of focal sites of transcription within human nuclei . In: The EMBO journal . tape 12 , no. 3 , March 1993, ISSN  0261-4189 , p. 1059-1065 , PMID 8458323 , PMC 413307 (free full text).
  3. ^ Iborra F: Active RNA polymerases are localized within discrete transcription "factories" in human nuclei . In: Journal of Cell Science . tape 109 , 1996, pp. 1427-1436 .
  4. ↑ Svitlana Melnik, Binwei Deng, Argyris Papantonis, Sabyasachi Baboo, Ian M Carr: The proteomes of transcription factories containing RNA polymerases I, II or III . In: Nature Methods . tape 8 , no. November 11 , 2011, ISSN  1548-7091 , p. 963–968 , doi : 10.1038 / nmeth.1705 , PMID 21946667 , PMC 3324775 (free full text) - ( nature.com [accessed August 8, 2019]).
  5. ↑ CH Eskiw, P. Fraser: Ultra structural study of transcription factories in mouse erythroblasts . In: Journal of Cell Science . tape 124 , no. 21 , November 1, 2011, ISSN  0021-9533 , p. 3676–3683 , doi : 10.1242 / jcs.087981 , PMID 22045738 , PMC 3215576 (free full text) - ( biologists.org [accessed August 8, 2019]).
  6. ↑ Svitlana Melnik, Binwei Deng, Argyris Papantonis, Sabyasachi Baboo, Ian M Carr: The proteomes of transcription factories containing RNA polymerases I, II or III . In: Nature Methods . tape 8 , no. November 11 , 2011, ISSN  1548-7091 , p. 963–968 , doi : 10.1038 / nmeth.1705 , PMID 21946667 , PMC 3324775 (free full text) - ( nature.com [accessed August 11, 2019]).
  7. ^ Argyris Papantonis, Peter R. Cook: Fixing the model for transcription: The DNA moves, not the polymerase . In: Transcription . tape 2 , no. 1 , January 2011, ISSN  2154-1264 , p. 41–44 , doi : 10.4161 / trns.2.1.14275 , PMID 21326910 , PMC 3023647 (free full text) - ( tandfonline.com [accessed August 8, 2019]).
  8. ↑ Cameron S Osborne, Lyubomira Chakalova, Karen E Brown, David Carter, Alice Horton: Active genes dynamically colocalize to shared sites of ongoing transcription . In: Nature Genetics . tape 36 , no. October 10 , 2004, ISSN  1061-4036 , p. 1065-1071 , doi : 10.1038 / ng1423 ( nature.com [accessed August 8, 2019]).
  9. ^ Iborra F: Active RNA polymerases are localized within discrete transcription "factories" in human nuclei . In: Journal of Cell Science . tape 109 , 1996, pp. 1427-1436 .
  10. ↑ Cameron S Osborne, Lyubomira Chakalova, Karen E Brown, David Carter, Alice Horton: Active genes dynamically colocalize to shared sites of ongoing transcription . In: Nature Genetics . tape 36 , no. October 10 , 2004, ISSN  1061-4036 , p. 1065-1071 , doi : 10.1038 / ng1423 ( nature.com [accessed August 8, 2019]).
  11. ^ Iborra F: Active RNA polymerases are localized within discrete transcription "factories" in human nuclei . In: Journal of Cell Science . tape 109 , 1996, pp. 1427-1436 .
  12. ^ S Lindquist: The Heat-Shock Response . In: Annual Review of Biochemistry . tape 55 , no. 1 , June 1986, ISSN  0066-4154 , pp. 1151–1191 , doi : 10.1146 / annurev.bi.55.070186.005443 ( annualreviews.org [accessed August 8, 2019]).
  13. ^ JA Mitchell, P. Fraser: Transcription factories are nuclear subcompartments that remain in the absence of transcription . In: Genes & Development . tape 22 , no. 1 , January 1, 2008, ISSN  0890-9369 , p. 20-25 , doi : 10.1101 / gad.454008 , PMID 18172162 , PMC 2151011 (free full text) - ( genesdev.org [accessed August 11, 2019]).
  14. ↑ M. Becker: Dynamic behavior of transcription factors on a natural promoter in living cells . In: EMBO Reports . tape 3 , no. 12 , December 16, 2002, p. 1188–1194 , doi : 10.1093 / embo-reports / kvf244 , PMID 12446572 , PMC 1308318 (free full text) - ( embopress.org [accessed August 8, 2019]).
  15. ↑ M. Becker: Dynamic behavior of transcription factors on a natural promoter in living cells . In: EMBO Reports . tape 3 , no. 12 , December 16, 2002, p. 1188–1194 , doi : 10.1093 / embo-reports / kvf244 , PMID 12446572 , PMC 1308318 (free full text) - ( embopress.org [accessed August 11, 2019]).
  16. ↑ Stefan Schoenfelder, Tom Sexton, Lyubomira Chakalova, Nathan F Cope, Alice Horton: Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells . In: Nature Genetics . tape 42 , no. 1 , January 2010, ISSN  1061-4036 , p. 53–61 , doi : 10.1038 / ng.496 , PMID 20010836 , PMC 3237402 (free full text) - ( nature.com [accessed August 9, 2019]).
  17. ↑ Marenduzzo D: Entropy-driven genome organization . In: Biophys J. J. 42, 2006, p. 3712-3721 .
  18. ^ Peter R. Cook: A Model for all Genomes: The Role of Transcription Factories . In: Journal of Molecular Biology . tape 395 , no. 1 , January 2010, p. 1–10 , doi : 10.1016 / j.jmb.2009.10.031 ( elsevier.com [accessed August 9, 2019]).
  19. ↑ IG Cowell, Z. Sondka, K. Smith, KC Lee, CM Manville: Model for MLL translocations in therapy-related leukemia involving topoisomerase II -mediated DNA strand breaks and gene proximity . In: Proceedings of the National Academy of Sciences . tape 109 , no. 23 , June 5, 2012, ISSN  0027-8424 , p. 8989-8994 , doi : 10.1073 / pnas.1204406109 , PMID 22615413 , PMC 3384169 (free full text) - ( pnas.org [accessed August 9, 2019]).