Control of Gene Expression

4 Key excerpts on "Control of Gene Expression"

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  eBook - ePub

  Eukaryotic Gene Regulation

  Volume I

  • Gerald M. Kolodny(Author)
  • 2018(Publication Date)
  • CRC Press

    (Publisher)

  Through these open gates we are integrated into the outside world; through these doors act sun, moon, and the integrality of our chemical and physical environment, not only on our senses and behavior but on the last molecule conditioned by one of our genes. Through these doors have organisms learned to respond to their environment by organization and adaptation. These are the gates of adaptation and evolution and the channels through which humans have learned to manipulate themsleves — for the good or the bad — by drugs.

  With these fundamental principles and mechanisms in mind, we may try now to extend our reflection in asking about the rationale of the development of the regulative system that we have discussed in extenso. One of the most central features of eukaryotic gene regulation is the appearance of multistep controls and of peripheral memories of information storage, and we may ask the question of their necessity and, hence, their development in evolution.

  FIGURE 20. Integration of control into the flow of coding information. This scheme shows the integration of the three distinct systems of information involved in gene expression: (1) the flow of coding information subject to control by the two other systems; (2) the network of regulating circuits based on macromolecular regulatory and service agents produced by transcription and translation; and (3) the system of low molecular weight effectors which condition and modulate in specific zones (cells or cell compartments) the activity of the controlling agents. All three components are integral parts of the regulatory circuits (cf. Figure 16 ) which carry further the carriers of genetic information to their ultimate expression. This compound system is open: information in form of macromolecular agents or effectors may be acquired from or released into the environment.

  A first reason relates to the requirements of efficiency and versality of regulation in a multiceli (or multiorgan) system which must adapt rapidly and locally to changes in physiological or functional state. To point out this necessity, we may recall the well-known phenomenon of diauxic growth of

  E. coli;109

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  RNA Regulation, 2 Volume Set

  • Robert A. Meyers(Author)
  • 2014(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  During the SOS response, cell division is also halted, so that any damaged chromosomes do not become segregated into the daughter cells. Consequently, during the SOS response, in addition to the DNA-repair enzymes a cell division-inhibitory protein is also expressed, at high levels.

  3 Regulation of Gene Expression in Eukaryotes

  In comparison to prokaryotes, the eukaryotes have a much more complex regulatory mechanism of transcription, with RNA splicing also playing an important role in the regulation of gene expression. In addition to the activation of gene structure, the polyadenylation, capping, transport to the cytoplasm, and translation of mRNA represent potent control points in the process of regulating gene expression. Five potential control points for regulating gene expression in eukaryotes are shown in Fig. 6 . The most important method of control is to regulate the initiation of transcription (i.e., the interaction of RNA polymerase with the promoter region), which may be demonstrated using a technique known as run-off transcription . In this case, the nuclei are first isolated from the cells and then incubated with radiolabeled nucleoside triphosphates. Under suitable conditions, unfinished transcripts will be completed, but no new transcripts will be synthesized; consequently, the RNA that is labeled by using this method will have been derived from those genes that started transcription at the time the nuclei were isolated. Subsequently, when the labeled RNA is used to probe DNA from a clone of genes under investigation, an absence of hybridization between the labeled RNA and the cloned DNA indicates that the DNA was not transcribed in the tissue. The use of this technique to examine several genes has led to the realization that an absence of gene expression does, indeed, result from an absence of transcription [27].

  Fig. 6

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  Molecular Pharmacology

  From DNA to Drug Discovery

  • John Dickenson, Fiona Freeman, Chris Lloyd Mills, Christian Thode, Shiva Sivasubramaniam(Authors)
  • 2012(Publication Date)
  • Wiley

    (Publisher)

  In addition, some lncRNAs are known to control the availability of essential proteins factors for cellular processes (e.g. splicing or transcription). One such example is MALAT-1 (metastasis-associated lung adenocarcinoma transcript-1; Ji et al., 2003), an lncRNA with an interesting biogenesis, subcellular location and function. In mammals, the mature MALAT-1 transcript has a length of ∼6.7 kb and derives from a larger precursor RNA (>7 kb), following RNase P cleavage. This also produces a smaller RNA, which is further processed to mascRNA (MALAT-1-associated RNA), a 61-nt tRNA-like small RNA (Wilusz et al., 2008). While mascRNA is exported to the cytoplasm, MALAT-1 is retained and enriched in nuclear ‘speckles’, that is, subnuclear bodies which play a role in the assembly of the pre-mRNA processing machinery. MALAT-1 is thought to modulate alternative splicing by sequestering inactive SR splicing factors into the speckles and altering their phosphorylation status (Tripathi et al., 2010). Experimentally-induced depletion of MALAT-1, which is normally present at high levels, leads to an increase in mislocalised and unphosphorylated SR proteins, and a higher rate of exon retention in mRNA transcripts. Likewise, trafficking of transcription factor NFAT (nuclear factor of activated T cells) in the cytoplasm can be controlled by NRON (ncRNA repressor of the NFAT; Willingham et al., 2005). Its interaction with the importin proteins in the nuclear envelope prevents NFAT from being transported into the nucleus and from activating genes. Increased NFAT activity, on the other hand, is observed if NRON is knockeddown. Both examples illustrate that important cellular processes can also be regulated indirectly by lncRNAs.

  8.10 Summary

  In this chapter we have seen that gene expression can be controlled at the level of transcription by transcription factors and their accessory proteins/complexes, non-coding RNAs and UTRs. The type of protein expressed is dependent upon splicing sites and the insertion/removal of specific exons. In addition, all of these factors are dependent upon SNP which can alter transcription factor and/or splicesome binding sites to prevent/enhance the expression of certain splice variants from a particular gene. All these elements can interact to produce cell-specific transcripts and hence responses to certain stimuli. This is an exciting area of research for the treatment of many types of disease.

  The human genome project has revealed that there are fewer genes in our chromosomes, than originally thought. This actually means is that different cells are likely to have varying levels of selective expression of the same groups of genes (rather than completely different sets of genes). This is mainly achieved by three processes (i) transcriptional regulation; (ii) post-transcriptional modification such as RNA editing; and (iii) translation/post-translational modifications. However transcriptional regulation is the most important in that it can coordinate the expression of gene products that act antagonistically in physiological processes. The BTFs are essential to initiate the transcription, whereas MTFs help to select, regulate and/or modify the transcriptional events. Thereby cells minimise the energy expenditure.

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  Measuring Gene Expression

  • Matthew Avison(Author)
  • 2008(Publication Date)
  • Taylor & Francis

    (Publisher)

  Escherichia coli, the Mar regulon (Miller and Sulavik, 1996) and how measurements of gene expression have been used to characterize its function.

  Figure 1.1

  Complications in functional genomics illustrated by the Mar regulon. The multiple antimicrobial drug resistance (Mar) regulon consists of two transcriptional regulators, MarR and MarA. The gene ompF and the operon acrAB encode a porin, through which antimicrobial drugs enter the cell, and an efflux pump which exports antimicrobials, respectively. Transcription of acrAB is under repression from the local regulator, AcrR and is activated through MarA binding upstream. Transcription of ompF is repressed when MarA binds upstream. MarR is a repressor for transcription of marA. Thus in (A), MarR binds to the promoter for marA, and represses transcription. AcrR binds to the promoter for acrAB, and represses transcription. There is no MarA to repress ompF transcription. Antimicrobials could flow into the cell through OmpF, and there would be no AcrAB available to pump them out again. In (B) an inducing ligand binds to MarR, reporting the presence of a toxic compound within the cell (e.g. an antimicrobial drug). This causes a conformational change in MarR, and marA transcription becomes derepressed. MarA then blocks transcription of ompF, but cannot significantly activate transcription of acrAB, because AcrR is still bound at the promoter, and its repressive effect is dominant. In this state, further antimicrobial entry would be limited, but the antimicrobial already inside the cell will not be pumped out. In (C) a second regulatory ligand has built up sufficiently to bind to AcrR and de-repress acrAB transcription. However, in the absence of MarA, transcription of acrAB would be low. In this case, however, MarA is available to activate transcription of acrAB, causing active efflux of the antimicrobial present within the cell. This illustrates the idea of multiple signals linking into a regulatory pathway. It also illustrates some of the inherent problems of studying regulation of gene expression. A deletion of marR would cause OmpF production to stop, so it might be concluded that MarR is an activator of ompF expression. Furthermore, mutations lead to activation of MarR, and so production of MarA may not always lead to production of AcrAB, thus it may be missed that MarA regulates acrAB

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