Academic literature on the topic 'Transcriptional interference'
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Journal articles on the topic "Transcriptional interference"
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O’Callaghan, Chris, Da Lin, and Thomas K. Hiron. "Intragenic transcriptional interference regulates the human immune ligand MICA." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 109.23. http://dx.doi.org/10.4049/jimmunol.200.supp.109.23.
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Abstract Regulation of MICA expression is incompletely understood, but human MICA can be upregulated in cancer cells, virus-infected cells and rapidly proliferating cells. Binding of MICA to the activating NKG2D receptor on cytotoxic immune cells promotes elimination of the cell expressing MICA. We noted that MICA has tandem promoters that drive overlapping forward transcription. We show that the MICA gene contains a conserved upstream promoter that expresses a non coding transcript. Transcription from the upstream promoter represses transcription from the standard downstream MICA promoter in cis through transcriptional interference. The effect of transcriptional interference depends on the strength of transcription from the upstream promoter and quantitative studies show that it is described by a simple reciprocal repressor function. The time course of transcriptional interference coincides with recruitment at the standard downstream promoter of factors involved in nucleosomal remodeling during transcription. Transcriptional interference is demonstrated in the regulation of MICA expression by the physiological inputs interferon-γ and interleukin-4, that both act through regulatory DNA elements in the upstream promoter. These findings have significant implications for the understanding of MICA expression. Transcription factors activating the downstream promoter will upregulate MICA expression, whereas transcription factors activating the upstream promoter will downregulated MICA expression. A genome-wide analysis indicates that transcriptional interference between tandem intragenic promoters may be involved in regulating the expression of multiple other human genes.
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Fang, Zhiming, Zhongming Zhao, Valsamma Eapen, and Raymond A. Clarke. "siRNA Mediate RNA Interference Concordant with Early On-Target Transient Transcriptional Interference." Genes 12, no. 8 (August 23, 2021): 1290. http://dx.doi.org/10.3390/genes12081290.
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Exogenous siRNAs are commonly used to regulate endogenous gene expression levels for gene function analysis, genotype–phenotype association studies and for gene therapy. Exogenous siRNAs can target mRNAs within the cytosol as well as nascent RNA transcripts within the nucleus, thus complicating siRNA targeting specificity. To highlight challenges in achieving siRNA target specificity, we targeted an overlapping gene set that we found associated with a familial form of multiple synostosis syndrome type 4 (SYSN4). In the affected family, we found that a previously unknown non-coding gene TOSPEAK/C8orf37AS1 was disrupted and the adjacent gene GDF6 was downregulated. Moreover, a conserved long-range enhancer for GDF6 was found located within TOSPEAK which in turn overlapped another gene which we named SMALLTALK/C8orf37. In fibroblast cell lines, SMALLTALK is transcribed at much higher levels in the opposite (convergent) direction to TOSPEAK. siRNA targeting of SMALLTALK resulted in post transcriptional gene silencing (PTGS/RNAi) of SMALLTALK that peaked at 72 h together with a rapid early increase in the level of both TOSPEAK and GDF6 that peaked and waned after 24 h. These findings indicated the following sequence of events: Firstly, the siRNA designed to target SMALLTALK mRNA for RNAi in the cytosol had also caused an early and transient transcriptional interference of SMALLTALK in the nucleus; Secondly, the resulting interference of SMALLTALK transcription increased the transcription of TOSPEAK; Thirdly, the increased transcription of TOSPEAK increased the transcription of GDF6. These findings have implications for the design and application of RNA and DNA targeting technologies including siRNA and CRISPR. For example, we used siRNA targeting of SMALLTALK to successfully restore GDF6 levels in the gene therapy of SYNS4 family fibroblasts in culture. To confidently apply gene targeting technologies, it is important to first determine the transcriptional interference effects of the targeting reagent and the targeted gene.
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Ingelbrecht, I., P. Breyne, K. Vancompernolle, A. Jacobs, M. Van Montagu, and A. Depicker. "Transcriptional interference in transgenic plants." Gene 109, no. 2 (December 1991): 239–42. http://dx.doi.org/10.1016/0378-1119(91)90614-h.
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SHEARWIN, K., B. CALLEN, and J. EGAN. "Transcriptional interference – a crash course." Trends in Genetics 21, no. 6 (June 2005): 339–45. http://dx.doi.org/10.1016/j.tig.2005.04.009.
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Hu, Xiao, Susan Eszterhas, Nicolas Pallazzi, Eric E. Bouhassira, Jennifer Fields, Osamu Tanabe, Scott A. Gerber, et al. "Transcriptional interference among the murine β-like globin genes." Blood 109, no. 5 (October 31, 2006): 2210–16. http://dx.doi.org/10.1182/blood-2006-06-029868.
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Abstract Mammalian β-globin loci contain multiple genes that are activated at different developmental stages. Studies have suggested that the transcription of one gene in a locus can influence the expression of the other locus genes. The prevalent model to explain this transcriptional interference is that all potentially active genes compete for locus control region (LCR) activity. To investigate the influence of transcription by the murine embryonic genes on transcription of the other β-like genes, we generated mice with deletions of the promoter regions of Ey and βh1 and measured transcription of the remaining genes. Deletion of the Ey and βh1 promoters increased transcription of βmajor and βminor 2-fold to 3-fold during primitive erythropoiesis. Deletion of Ey did not affect βh1 nor did deletion of βh1 affect Ey, but Ey deletion uniquely activated transcription from βh0, a β-like globin gene immediately downstream of Ey. Protein analysis showed that βh0 encodes a translatable β-like globin protein that can pair with alpha globin. The lack of transcriptional interference between Ey and βh1 and the gene-specific repression of βh0 did not support LCR competition among the embryonic genes and suggested that direct transcriptional interference from Ey suppressed βh0.
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Palmer, Adam C., J. Barry Egan, and Keith E. Shearwin. "Transcriptional interference by RNA polymerase pausing and dislodgement of transcription factors." Transcription 2, no. 1 (January 2011): 9–14. http://dx.doi.org/10.4161/trns.2.1.13511.
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Ard, Ryan, and Robin C. Allshire. "Transcription-coupled changes to chromatin underpin gene silencing by transcriptional interference." Nucleic Acids Research 44, no. 22 (September 8, 2016): 10619–30. http://dx.doi.org/10.1093/nar/gkw801.
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Chan, H., S. Hartung, and M. Breindl. "Retrovirus-induced interference with collagen I gene expression in Mov13 fibroblasts is maintained in the absence of DNA methylation." Molecular and Cellular Biology 11, no. 1 (January 1991): 47–54. http://dx.doi.org/10.1128/mcb.11.1.47-54.1991.
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We have studied the role of DNA methylation in repression of the murine alpha 1 type I collagen (COL1A1) gene in Mov13 fibroblasts. In Mov13 mice, a retroviral provirus has inserted into the first intron of the COL1A1 gene and blocks its expression at the level of transcriptional initiation. We found that regulatory sequences in the COL1A1 promoter region that are involved in the tissue-specific regulation of the gene are unmethylated in collagen-expressing wild-type fibroblasts and methylated in Mov13 fibroblasts, confirming and extending earlier observations. To directly assess the role of DNA methylation in the repression of COL1A1 gene transcription, we treated Mov13 fibroblasts with the demethylating agent 5-azacytidine. This treatment resulted in a demethylation of the COL1A1 regulatory sequences but failed to activate transcription of the COL1A1 gene. Moreover, the 5-azacytidine treatment induced a transcription-competent chromatin structure in the retroviral sequences but not in the COL1A1 promoter. In DNA transfection and microinjection experiments, we found that the provirus interfered with transcriptional activity of the COL1A1 promoter in Mov13 fibroblasts but not in Xenopus laevis oocytes. In contrast, the wild-type COL1A1 promoter was transcriptionally active in Mov13 fibroblasts. These experiments showed that the COL1A1 promoter is potentially transcriptionally active in the presence of proviral sequences and that Mov13 fibroblasts contain the trans-acting factors required for efficient COL1A1 gene expression. Our results indicate that the provirus insertion in Mov13 can inactivate COL1A1 gene expression at several levels. It prevents the developmentally regulated establishment of a transcription-competent methylation pattern and chromatin structure of the COL1A1 domain and, in the absence of DNA methylation, appears to suppress the COL1A1 promoter in a cell-specific manner, presumably by assuming a dominant chromatin structure that may be incompatible with transcriptional activity of flanking cellular sequences.
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Chan, H., S. Hartung, and M. Breindl. "Retrovirus-induced interference with collagen I gene expression in Mov13 fibroblasts is maintained in the absence of DNA methylation." Molecular and Cellular Biology 11, no. 1 (January 1991): 47–54. http://dx.doi.org/10.1128/mcb.11.1.47.
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We have studied the role of DNA methylation in repression of the murine alpha 1 type I collagen (COL1A1) gene in Mov13 fibroblasts. In Mov13 mice, a retroviral provirus has inserted into the first intron of the COL1A1 gene and blocks its expression at the level of transcriptional initiation. We found that regulatory sequences in the COL1A1 promoter region that are involved in the tissue-specific regulation of the gene are unmethylated in collagen-expressing wild-type fibroblasts and methylated in Mov13 fibroblasts, confirming and extending earlier observations. To directly assess the role of DNA methylation in the repression of COL1A1 gene transcription, we treated Mov13 fibroblasts with the demethylating agent 5-azacytidine. This treatment resulted in a demethylation of the COL1A1 regulatory sequences but failed to activate transcription of the COL1A1 gene. Moreover, the 5-azacytidine treatment induced a transcription-competent chromatin structure in the retroviral sequences but not in the COL1A1 promoter. In DNA transfection and microinjection experiments, we found that the provirus interfered with transcriptional activity of the COL1A1 promoter in Mov13 fibroblasts but not in Xenopus laevis oocytes. In contrast, the wild-type COL1A1 promoter was transcriptionally active in Mov13 fibroblasts. These experiments showed that the COL1A1 promoter is potentially transcriptionally active in the presence of proviral sequences and that Mov13 fibroblasts contain the trans-acting factors required for efficient COL1A1 gene expression. Our results indicate that the provirus insertion in Mov13 can inactivate COL1A1 gene expression at several levels. It prevents the developmentally regulated establishment of a transcription-competent methylation pattern and chromatin structure of the COL1A1 domain and, in the absence of DNA methylation, appears to suppress the COL1A1 promoter in a cell-specific manner, presumably by assuming a dominant chromatin structure that may be incompatible with transcriptional activity of flanking cellular sequences.
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Jorgensen, Victoria, Jingxun Chen, Helen Vander Wende, Devon E. Harris, Alicia McCarthy, Shane Breznak, Siu Wah Wong-Deyrup, et al. "Tunable Transcriptional Interference at the Endogenous Alcohol Dehydrogenase Gene Locus in Drosophila melanogaster." G3: Genes|Genomes|Genetics 10, no. 5 (March 25, 2020): 1575–83. http://dx.doi.org/10.1534/g3.119.400937.
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Neighboring sequences of a gene can influence its expression. In the phenomenon known as transcriptional interference, transcription at one region in the genome can repress transcription at a nearby region in cis. Transcriptional interference occurs at a number of eukaryotic loci, including the alcohol dehydrogenase (Adh) gene in Drosophila melanogaster. Adh is regulated by two promoters, which are distinct in their developmental timing of activation. It has been shown using transgene insertion that when the promoter distal from the Adh start codon is deleted, transcription from the proximal promoter becomes de-regulated. As a result, the Adh proximal promoter, which is normally active only during the early larval stages, becomes abnormally activated in adults. Whether this type of regulation occurs in the endogenous Adh context, however, remains unclear. Here, we employed the CRISPR/Cas9 system to edit the endogenous Adh locus and found that removal of the distal promoter also resulted in the untimely expression of the proximal promoter-driven mRNA isoform in adults, albeit at lower levels than previously reported. Importantly, transcription from the distal promoter was sufficient to repress proximal transcription in larvae, and the degree of this repression was dependent on the degree of distal promoter activity. Finally, upregulation of the distal Adh transcript led to the enrichment of histone 3 lysine 36 trimethylation over the Adh proximal promoter. We conclude that the endogenous Adh locus is developmentally regulated by transcriptional interference in a tunable manner.
Dissertations / Theses on the topic "Transcriptional interference"
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Greger, Ingo Harald. "Transcriptional interference between highly expressed eukaryotic genes." Thesis, University of Oxford, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298678.
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Watts, Beth Rosina. "Investigating mechanisms of transcriptional interference in Schizosaccharomyces pombe." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:c919478f-21e9-4061-81aa-4ec1ae41d223.
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Eukaryotic cells transcribe a vast array of non-coding RNAs, most of which have not been assigned a functional role. The work presented here reveals a novel mechanism of transcriptional repression that is mediated by the non-coding RNA prt (pho1-repressing transcript). The prt transcript is shown to recruit a histone deacetylase, Clr3, to repress pho1. This gene encodes a secreted acid phosphatase essential for phosphate acquisition in fission yeast. In the presence of phosphate, prt is produced from an upstream promoter and leads to silencing of pho1. Thus far, this has been explained by prt transcription leading to deposition of repressive methylation over the locus. However, this explanation is known to be incomplete since deletion of the only known histone methyltransferase does not lead to pho1 induction comparable to deletion of the prt promoter. This suggests that another mechanism must be involved in mediating transcriptional interference via non-coding transcription. In the present study the putative ncRNA-binding protein Seb1, together with the chromatin modifying complex SHREC, is demonstrated to associate with prt to elicit silencing of pho1 by a mechanism that is independent of H3K9 methylation and instead relies on deacetylase activity provided by the Clr3 component of SHREC. These data reveal a previously uncharacterised layer of ncRNA-mediated gene regulation and provide important conceptual advances in understanding the mechanisms governing the phenomenon known as transcriptional interference.
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Chiu, Ya-Lin. "HIV-1 Gene Expression: Transcriptional Regulation and RNA Interference Studies: a Dissertation." eScholarship@UMMS, 2003. https://escholarship.umassmed.edu/gsbs_diss/118.
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Gene expression of human immunodeficiency virus type-1 (HIV-1), which causes Acquired Immunodeficiency Syndrome (AIDS), is regulated at the transcriptional level, where negative factors can block elongation that is overcome by HIV Tat protein and P-TEFb. P-TEFb, a positive elongation transcription factor with two subunits, CDK9 and Cyclin T1 (CycT1), catalyzes Tat-dependent phosphorylation of Ser-5 in the Pol II C-terminal domain (CTD), allowing production of longer mRNAs. Ser-5 phosphorylation enables the CTD to recruit mammalian mRNA capping enzyme (Mce1) and stimulate its guanylyltransferase activity. This dissertation demonstrates that stable binding of Mce1 and cap methyltransferase to template-engaged Pol II depends on CTD phosphorylation, but not on nascent RNA. Capping and methylation doesn't occur until nascent pre-mRNA become 19-22 nucleotides long. A second and novel pathway for recruiting and activating Mce1 involved direct physical interaction between the CTD, Tat and Mce1. Tat stimulated the guanylyltransferase and triphosphatase activities of Mce1, thereby enhancing the otherwise low efficiency of cotranscriptional capping of HIV mRNA. These findings imply that multiple mechanisms exist for coupling transcription elongation and mRNA processing at a checkpoint critical to HIV gene expression.
To elucidate P-TEFb's function in human (HeLa) cells, RNA interference (RNAi) was used to degrade mRNA for hCycT1 or CDK9. Down-regulation of P-TEFb expression by RNAi can be achieved without causing major toxic or lethal effects and can control Tat transactivation and HIV replication in host cells. High-density oligonucleotide arrays were used to determine the effect of P-TEFb knockdown on global gene expression. Of 44,928 human genes analyzed, 25 were down-regulated and known or likely to be involved in cell proliferation and differentiation. These results provide new insight into P-TEFb function, its potent role in early embryonic development and strong evidence that P-TEFb is a new target for developing AIDS and cancer therapies.
To fulfill the promise of RNAi for treating infectious and human genetic diseases, structural and functional mechanisms underlying RNAi in human cells were studied. The status of the 5' hydroxyl terminus of the antisense strand of short interfering RNA (siRNA) duplexes determined RNAi activity, while a 3' terminus block was tolerated in vivo. A perfect A-form helix in siRNA was not required for RNAi, but was required for antisense-target RNA duplexes. Strikingly, crosslinking siRNA duplexes with psoralen did not completely block RNAi, indicating that complete unwinding of the siRNA helix is not necessary for RNAi in vivo. These results suggest that RNA amplification by RNA-dependent RNA polymerase is not essential for RNAi in human cells.
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Thomson, Gabrielle Anne Biotechnology & Biomolecular Sciences Faculty of Science UNSW. "Retroelements as controlling elements in mammals." Awarded by:University of New South Wales. Biotechnology and Biomolecular Sciences, 2006. http://handle.unsw.edu.au/1959.4/26203.
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Retroelements are genomic parasites which make up ~42% of the human genome and 38% of the mouse genome. Most are degenerate, but a large number have relatively intact promoter elements, suggesting that they are capable of transcription. Transcriptionally active retroelements can perturb normal transcription units in their vicinity through a variety of mechanisms, leading to phenotypic effects and in some cases disease. This phenomenon of transcriptional interference has been observed in organisms as diverse as maize, Drosophila, and the mouse. We analysed the extent of retroelement transcription in normal and diseased tissues, by searching the mouse and human EST databases for transcripts originating in retroelement promoters, and found a large number of transcripts from LINEs, SINEs and ERVs. Retroelement transcripts were found to be initiated in both sense and antisense orientations, and to be equally as common in normal and diseased tissue. Several of these transcripts were chimeric, appearing to initiate in retroelements and reading through to cellular genes, suggestive of transcriptional interference. We have used transposon display to identify and recover retroelement transcripts in the mouse. Transcripts initiated in LINE, SINE and ERV promoters are numerous, and many are chimeric with cellular genes. Although the numbers of recovered chimeric transcripts are too large to permit rigorous analysis of more than a small proportion, some of those we have studied further appear to be authentic transcripts that may represent interference with the canonical promoters of the genes in question. Our results suggest that transcriptional interference by retroelements may be a relatively common occurrence in mammals.
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Puram, Rishi Venkata. "Defining and Targeting Transcriptional Pathways in Leukemia Stem Cells." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13070042.
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Acute myeloid leukemia (AML) is a clonal neoplastic disorder organized as a cellular hierarchy, with the self-renewing leukemia stem cell (LSC) at the apex. Recurrent mutations in transcription factors (TF) and epigenetic regulators suggest that AML is driven by aberrant transcriptional circuits, but these circuits have not been fully defined in an LSC model. To study transcriptional mechanisms relevant to leukemogenesis in vivo, we generated a murine serial transplantation model of MLL-AF9-driven, myelomonocytic leukemia with genetically- and phenotypically-defined LSCs. Using this model, we pursued two related lines of investigation.
First, we performed an in vivo RNA interference (RNAi) screen to identify transcription factors required for LSC function. This screen highlighted the circadian rhythm TFs, Clock and Bmal1, as genes essential for the survival of murine leukemia cells, and we validated this finding with CRISPR/Cas-based genome editing and knockdown studies in AML cell lines. Utilizing luciferase reporter mice to track expression of the circadian target gene Per2, we demonstrated that both leukemic and normal hematopoietic cells have the capacity for oscillating, circadian-dependent gene expression. Importantly, using murine knockout models, we found that normal hematopoietic stem and progenitor cells (HSPC), in contrast to leukemia cells, do not depend on Bmal1. We further demonstrated that selective depletion of LSCs following circadian perturbation is mediated through enhanced myeloid differentiation. ChIP-Seq studies revealed that the circadian rhythm network is integrally connected to the LSC self-renewal circuitry and highlighted putative Clock/Bmal1 targets in leukemia, providing a mechanistic basis for our findings.
Second, we performed a functional and genomic characterization of our MLL-AF9 serial transplantation model to explore mechanisms of disease evolution and clonal selection in AML. Limiting dilution studies demonstrated that serial transplantation results in a reduction in disease latency, dramatic enrichment of leukemia-initiating cells (LIC), and reconfiguration of the LSC hierarchy. While mutations in known AML-associated genes were not linked to disease progression, RNA-sequencing (RNA-Seq) demonstrated that the increase in LIC frequency in serially transplanted leukemias is driven by changes in cell cycle and differentiation. In aggregate, these studies offer insights into the biological mechanisms regulating LSC self-renewal and disease evolution in AML.
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Racanelli, Alexandra. "TRANSCRIPTIONAL, EPIGENETIC, AND SIGNAL EVENTS IN ANTIFOLATE THERAPEUTICS." VCU Scholars Compass, 2009. http://scholarscompass.vcu.edu/etd/1876.
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A targeted approach to the development of antifolate therapies has been sought for many years. Central to the success of such development is an understanding of the molecular mechanisms dictating the sensitivity of cells to antifolates and the fundamental differences of these processes between normal and neoplastic phenotypes. This dissertation addressed transcriptional mechanisms and cell-signaling events responsible for the efficacy of antifolate therapies. Transcriptional processes and cell signaling pathways are often aberrant in neoplastic tissues, providing a potential point of distinction between a normal and neoplastic cellular state. Folylpolyglutamate synthetase (FPGS) catalyzes the formation of poly-γ-glutamate derivatives of folates and antifolates, which permits intracellular retention and accumulation of these compounds. The mouse fpgs gene uses two distant promoters to produce functionally distinct isozymes in a tissue-specific pattern. We questioned how the two promoters were differentially controlled. An analysis of DNA methylation and histone post-translational modifications across the length of the mouse fpgs gene showed that epigenetic mechanisms contributed to the tissue-specific control of the upstream (P1), but not the downstream (P2) fpgs promoter. RNAPII complexes and general transcription factors were present over P1 only when P1 was transcribed, but these components were present over P2 in most tissues, and promoter-proximal pausing was evident in brain. Clear promoter occlusion was found over P2 in liver. These studies concluded that tissue-specific coordination of dual promoters required multiple interacting controls. The mammalian target of rapamycin (mTOR) controls protein translation initiation, and is central to a cell-signaling pathway rich in tumor suppressor and oncogenic proteins. mTOR dysregulation is a common feature of several human cancers and inhibition of this protein has been sought as an ideal cancer drug target. We have determined that antifolates inhibiting the two folate-dependent steps of purine synthesis (GART or AICART) activate AMP-dependent protein kinase (AMPK) and inhibit mTOR. The mechanism of AMPK stimulation appears to be mediated by either nucleotide depletion (GART inhibitors), or ZMP accumulation (AICART inhibitors). These studies discovered a new mechanism for antifolates that surprisingly defines them as molecularly targeted therapeutics.
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Mulder, Jaap. "Towards treatment of cholestatic liver disease in children via interference with transcriptional regulation of hepatic transport systems." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 2009. http://irs.ub.rug.nl/ppn/.
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Chery, Alicia. "Rôle de la transcription pervasive antisens chez Saccharomyces cerevisiae dans la régulation de l'expression des gènes." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066191/document.
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L'expression des gènes est finement régulée dans la cellule et soumise à de multiples contrôles-qualité. Cette régulation intervient à différents niveaux, de façon à garantir une synthèse efficace des produits fonctionnels de l'expression génique, et pour assurer une adaptation à un changement environnemental. Notamment, les régulations transcriptionnelles sont cruciales pour contrôler la cinétique et le niveau d'expression des gènes. La transcription pervasive est une transcription généralisée non-codante et instable qui fut révélée chez la levure Saccharomyces cerevisiae. Bien que son potentiel régulateur ait été démontré de façon ponctuelle, la question de sa fonctionnalité globale restait ouverte. Lors de ma thèse, j'ai pu montrer l'existence de phénomènes multiples d'interférence transcriptionnelle liés à la transcription pervasive, pour co-réguler un ensemble de gènes entre la phase exponentielle et la quiescence. En effet, la transcription non-codante en antisens des gènes concernés conduit à leur répression, dans des conditions où ils ne doivent pas être exprimés. Le mécanisme de répression fait intervenir des modifications de la chromatine. La levure bourgeonnante, dépourvue de la machinerie d'ARN interférence, présente donc un système fin de régulation de l'expression génique utilisant la transcription pervasiveIn the cell, gene expression is finely tuned and is submitted to different quality-controls. Gene are regulated at different expression levels in order to guarantee a proper synthesis of functional products, and to ensure an optimal adaptation to environmental changes. In particular, transcriptional regulations are critical for gene expression level and kinetics.Pervasive transcription, defined as a generalized non-coding and unstable transcription, was discovered in the yeast Saccharomyces cerevisiae. Although its regulatory potential was punctually shown, the question of its global functionality still remained. During my PhD, I could show the existence of numerous transcriptional interference mechanisms involved in the co-regulation of a group of genes between exponential phase and quiescence. Indeed, non-coding transcription in antisense to genes promoter leads to its repression in conditions where they have to be switched off. The repression mechanism is allowed by chromatin modifications.Hence, budding yeast that lacks RNA interference machinery has developed a fine regulation system using pervasive transcription
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Haley, Benjamin. "A Biochemical Dissection of the RNA Interference Pathway in Drosophila melanogaster: A Dissertation." eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/9.
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In diverse eukaryotic organisms, double-stranded RNA (dsRNA) induces robust silencing of cellular RNA cognate to either strand of the input dsRNA; a phenomenon now known as RNA interference (RNAi). Within the RNAi pathway, small, 21 nucleotide (nt) duplexed RNA, dubbed small interfering RNAs (siRNAs), derived from the longer input dsRNA, guide the RNA induced silencing complex (RISC) to destroy its target RNA. Due to its ability to silence virtually any gene, whether endogenous or exogenous, in a variety of model organisms and systems, RNAi has become a valuable laboratory tool, and is even being heralded as a potential therapy for an array of human diseases. In order to understand this complex and unique pathway, we have undertaken the biochemical characterization of RNAi in the model insect, Drosophila melanogaster.
To begin, we investigated the role of ATP in the RNAi pathway. Our data reveal several ATP-dependent steps and suggest that the RNAi reaction comprises as least five sequential stages: ATP-dependent processing of double-stranded RNA into siRNAs, ATP-independent incorporation of siRNAs into an inactive ~360 kDa protein/RNA complex, ATP-dependent unwinding of the siRNA duplex to generate an active complex, ATP-dependent activation of RISC following siRNA unwinding, and ATP-independent recognition and cleavage of the RNA target. In addition, ATP is used to maintain 5´ phosphates on siRNAs, and only siRNAs with these characteristic 5´ phosphates gain entry into the RNAi pathway.
Next, we determined that RISC programmed exogenously with an siRNA, like that programmed endogenously with microRNAs (miRNAs), is an enzyme. However, while RISC behaves like a classical Michaelis-Menten enzyme in the presence of ATP, without ATP, multiple rounds of catalysis are limited by release of RISC-produced cleavage products. Kinetic analysis of RISC suggests that different regions of the siRNA play distinct roles in the cycle of target recognition, cleavage and product release. Bases near the siRNA 5´ end disproportionately contribute to target RNA-binding energy, whereas base pairs formed by the central and 3´ region of the siRNA provide helical geometry required for catalysis. Lastly, the position of the scissile phosphate is determined during RISC assembly, before the siRNA encounters its RNA target.
In the course of performing the kinetic assessment of RISC, we observed that when siRNAs are designed with regard to 'functional asymmetry' (by unpairing the 5´ terminal nucleotide of the siRNA's guide strand, i.e. the strand anti-sense to the target RNA), not all of the RISC formed was active for target cleavage. We observed, somewhat paradoxically, that increased siRNA unwinding and subsequent accumulation of single-stranded RNA into RISC led to reduced levels of active RISC formation. This inactive RISC did not act as a competitor for the active fraction. In order to characterize this non-cleaving complex, we performed a series of protein-siRNA photo-crosslinking assays. From these assays we found that thermodynamic stability and termini structure plays a role in determining which proteins an siRNA will associate with, and how association occurs. Furthermore, we have found, by means of the photo-crosslinking assays, that siRNAs commingle with components of the miRNA pathway, particularly Ago1, suggesting overlapping functions or crosstalk for factors thought to be involved in separate, distinct pathways.
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Chery, Alicia. "Rôle de la transcription pervasive antisens chez Saccharomyces cerevisiae dans la régulation de l'expression des gènes." Electronic Thesis or Diss., Paris 6, 2017. http://www.theses.fr/2017PA066191.
Full textAbstract:
L'expression des gènes est finement régulée dans la cellule et soumise à de multiples contrôles-qualité. Cette régulation intervient à différents niveaux, de façon à garantir une synthèse efficace des produits fonctionnels de l'expression génique, et pour assurer une adaptation à un changement environnemental. Notamment, les régulations transcriptionnelles sont cruciales pour contrôler la cinétique et le niveau d'expression des gènes. La transcription pervasive est une transcription généralisée non-codante et instable qui fut révélée chez la levure Saccharomyces cerevisiae. Bien que son potentiel régulateur ait été démontré de façon ponctuelle, la question de sa fonctionnalité globale restait ouverte. Lors de ma thèse, j'ai pu montrer l'existence de phénomènes multiples d'interférence transcriptionnelle liés à la transcription pervasive, pour co-réguler un ensemble de gènes entre la phase exponentielle et la quiescence. En effet, la transcription non-codante en antisens des gènes concernés conduit à leur répression, dans des conditions où ils ne doivent pas être exprimés. Le mécanisme de répression fait intervenir des modifications de la chromatine. La levure bourgeonnante, dépourvue de la machinerie d'ARN interférence, présente donc un système fin de régulation de l'expression génique utilisant la transcription pervasiveIn the cell, gene expression is finely tuned and is submitted to different quality-controls. Gene are regulated at different expression levels in order to guarantee a proper synthesis of functional products, and to ensure an optimal adaptation to environmental changes. In particular, transcriptional regulations are critical for gene expression level and kinetics.Pervasive transcription, defined as a generalized non-coding and unstable transcription, was discovered in the yeast Saccharomyces cerevisiae. Although its regulatory potential was punctually shown, the question of its global functionality still remained. During my PhD, I could show the existence of numerous transcriptional interference mechanisms involved in the co-regulation of a group of genes between exponential phase and quiescence. Indeed, non-coding transcription in antisense to genes promoter leads to its repression in conditions where they have to be switched off. The repression mechanism is allowed by chromatin modifications.Hence, budding yeast that lacks RNA interference machinery has developed a fine regulation system using pervasive transcription
Book chapters on the topic "Transcriptional interference"
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Morris, Kevin V. "RNA-Mediated Transcriptional Gene Silencing in Human Cells." In RNA Interference, 211–24. Berlin, Heidelberg: Springer Berlin Heidelberg, 2008. http://dx.doi.org/10.1007/978-3-540-75157-1_10.
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Kjos, Morten. "Transcriptional Knockdown in Pneumococci Using CRISPR Interference." In Methods in Molecular Biology, 89–98. New York, NY: Springer New York, 2019. http://dx.doi.org/10.1007/978-1-4939-9199-0_8.
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Hawkins, John S., Spencer Wong, Jason M. Peters, Ricardo Almeida, and Lei S. Qi. "Targeted Transcriptional Repression in Bacteria Using CRISPR Interference (CRISPRi)." In Methods in Molecular Biology, 349–62. New York, NY: Springer New York, 2015. http://dx.doi.org/10.1007/978-1-4939-2687-9_23.
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Forloni, Matteo, Thuy Ho, Lisha Sun, and Narendra Wajapeyee. "Large-Scale RNA Interference Screening to Identify Transcriptional Regulators of a Tumor Suppressor Gene." In Methods in Molecular Biology, 261–68. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-6518-2_19.
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Ricci, Angela, Silvia Sabbadini, Laura Miozzi, Bruno Mezzetti, and Emanuela Noris. "Host-induced gene silencing and spray-induced gene silencing for crop protection against viruses." In RNAi for plant improvement and protection, 72–85. Wallingford: CABI, 2021. http://dx.doi.org/10.1079/9781789248890.0008.
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Abstract Since the beginning of agriculture, plant virus diseases have been a strong challenge for farming. Following its discovery at the very beginning of the 1990s, the RNA interference (RNAi) mechanism has been widely studied and exploited as an integrative tool to obtain resistance to viruses in several plant species, with high target-sequence specificity. In this chapter, we describe and review the major aspects of host-induced gene silencing (HIGS), as one of the possible plant defence methods, using genetic engineering techniques. In particular, we focus our attention on the use of RNAi-based gene constructs to introduce stable resistance in host plants against viral diseases, by triggering post-transcriptional gene silencing (PTGS). Recently, spray-induced gene silencing (SIGS), consisting of the topical application of small RNA molecules to plants, has been explored as an alternative tool to the stable integration of RNAi-based gene constructs in plants. SIGS has great and innovative potential for crop defence against different plant pathogens and pests and is expected to raise less public and political concern, as it does not alter the genetic structure of the plant.
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Ricci, Angela, Silvia Sabbadini, Laura Miozzi, Bruno Mezzetti, and Emanuela Noris. "Host-induced gene silencing and spray-induced gene silencing for crop protection against viruses." In RNAi for plant improvement and protection, 72–85. Wallingford: CABI, 2021. http://dx.doi.org/10.1079/9781789248890.0072.
Full textAbstract:
Abstract Since the beginning of agriculture, plant virus diseases have been a strong challenge for farming. Following its discovery at the very beginning of the 1990s, the RNA interference (RNAi) mechanism has been widely studied and exploited as an integrative tool to obtain resistance to viruses in several plant species, with high target-sequence specificity. In this chapter, we describe and review the major aspects of host-induced gene silencing (HIGS), as one of the possible plant defence methods, using genetic engineering techniques. In particular, we focus our attention on the use of RNAi-based gene constructs to introduce stable resistance in host plants against viral diseases, by triggering post-transcriptional gene silencing (PTGS). Recently, spray-induced gene silencing (SIGS), consisting of the topical application of small RNA molecules to plants, has been explored as an alternative tool to the stable integration of RNAi-based gene constructs in plants. SIGS has great and innovative potential for crop defence against different plant pathogens and pests and is expected to raise less public and political concern, as it does not alter the genetic structure of the plant.
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Misa, Joshua, and Cory Schwartz. "CRISPR Interference and Activation to Modulate Transcription in Yarrowia lipolytica." In Methods in Molecular Biology, 95–109. New York, NY: Springer US, 2021. http://dx.doi.org/10.1007/978-1-0716-1414-3_6.
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Ravelonandro, Michel, and Pascal Briard. "Biogenesis and functional RNAi in fruit trees." In RNAi for plant improvement and protection, 40–46. Wallingford: CABI, 2021. http://dx.doi.org/10.1079/9781789248890.0005.
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Abstract In plants, genome expression is linked to the transcribed mRNAs that are synthesized by RNA polymerase. Following its move to the cytoplasm, the generated mRNA is briefly translated to the encoded protein. If transcription and translation are dependent on the family of RNA polymerase, these two phenomena could be interfered with through the process designated as gene regulation. Thus, large molecules of RNA (single-stranded or double-stranded) consequently sliced into small molecules produce nascent small interfering RNA ranging from 21 to 27 nucleotides. This chapter revisits the biogenesis of these two types of RNAi, miRNA and siRNA, and notably their involvement in plant gene regulation. Following their sequential transcription and their specific involvement, we will consider the sources and roles of RNA interference in plants and we will look at their detection in fruit crops. We discuss their applications and the risk assessment studies in fruit crops.
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Ravelonandro, Michel, and Pascal Briard. "Biogenesis and functional RNAi in fruit trees." In RNAi for plant improvement and protection, 40–46. Wallingford: CABI, 2021. http://dx.doi.org/10.1079/9781789248890.0040.
Full textAbstract:
Abstract In plants, genome expression is linked to the transcribed mRNAs that are synthesized by RNA polymerase. Following its move to the cytoplasm, the generated mRNA is briefly translated to the encoded protein. If transcription and translation are dependent on the family of RNA polymerase, these two phenomena could be interfered with through the process designated as gene regulation. Thus, large molecules of RNA (single-stranded or double-stranded) consequently sliced into small molecules produce nascent small interfering RNA ranging from 21 to 27 nucleotides. This chapter revisits the biogenesis of these two types of RNAi, miRNA and siRNA, and notably their involvement in plant gene regulation. Following their sequential transcription and their specific involvement, we will consider the sources and roles of RNA interference in plants and we will look at their detection in fruit crops. We discuss their applications and the risk assessment studies in fruit crops.
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Hampson, Ian, Gavin Batman, and Thomas Walker. "RNA interference technology." In Tools and Techniques in Biomolecular Science. Oxford University Press, 2013. http://dx.doi.org/10.1093/hesc/9780199695560.003.0006.
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This chapter explains the RNA interference (RNAi) machinery that regulates post-transcriptional gene silencing. The RNAi technology is considered a vital tool in basic molecular and cellular genetic research, functional genomics, gene expression profiling, drug discovery, prospective disease targeting, and therapies. The chapter describes how the two main classes of small regulatory RNAs-short interfering RNA (siRNA) and microRNA (miRNA)-are generated and how they silence gene expression. It gives an overview of the RNAi pathway and looks at the two main approaches currently used to silence gene expression in vitro , namely, the siRNA technology and the short hairpin RNA (shRNA) technology. Moreover, it discusses the advantages and limitations of the two. The chapter also explores the therapeutic possibilities available using targeted gene silencing.
Conference papers on the topic "Transcriptional interference"
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Shein, M. Yu, G. F. Burkhanova, and I. V. Maksimov. "The effect of bacterial strains on the transcriptional activity of genes of the RNA interference system in wheat (Triticum) infected with Septoria." In 2nd International Scientific Conference "Plants and Microbes: the Future of Biotechnology". PLAMIC2020 Organizing committee, 2020. http://dx.doi.org/10.28983/plamic2020.222.
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In wheat, the level of expression of DCL4 and AGO1 genes correlated with resistance to the pathogen S. nodorum. The transcriptional activity of these genes increased when treated with strains of B. subtilis 26D and B. thuringiensis 11.
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Oakes, Christopher C., Yoon Jung Park, Michael Boutros, and Christoph Plass. "Abstract B6: Revealing DAPK1 transcriptional regulation by RNA interference screening with an integrated BAC‐reporter system." In Abstracts: First AACR International Conference on Frontiers in Basic Cancer Research--Oct 8–11, 2009; Boston MA. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/0008-5472.fbcr09-b6.
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Zhu, Jingjing, Jeroen Declercq, Karen Willekens, John WM Creemers, Alphons JM Vermorken, and Willem JM Van de Ven. "Abstract 1981: Interference of the polyphenolic compound curcumin with expression regulation of target genes of thePLAG1oncogenic transcription factor." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-1981.
Full textReports on the topic "Transcriptional interference"
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Dubcovsky, Jorge, Tzion Fahima, Ann Blechl, and Phillip San Miguel. Validation of a candidate gene for increased grain protein content in wheat. United States Department of Agriculture, January 2007. http://dx.doi.org/10.32747/2007.7695857.bard.
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High Grain Protein Content (GPC) of wheat is important for improved nutritional value and industrial quality. However, selection for this trait is limited by our poor understanding of the genes involved in the accumulation of protein in the grain. A gene with a large effect on GPC was detected on the short arm of chromosome 6B in a Triticum turgidum ssp. dicoccoides accession from Israel (DIC, hereafter). During the previous BARD project we constructed a half-million clones Bacterial Artificial Chromosome (BAC) library of tetraploid wheat including the high GPC allele from DIC and mapped the GPC-B1 locus within a 0.3-cM interval. Our long-term goal is to provide a better understanding of the genes controlling grain protein content in wheat. The specific objectives of the current project were to: (1) complete the positional cloning of the GPC-B1 candidate gene; (2) characterize the allelic variation and (3) expression profile of the candidate gene; and (4) validate this gene by using a transgenic RNAi approach to reduce the GPC transcript levels. To achieve these goals we constructed a 245-kb physical map of the GPC-B1 region. Tetraploid and hexaploid wheat lines carrying this 245-kb DIC segment showed delayed senescence and increased GPC and grain micronutrients. The complete sequencing of this region revealed five genes. A high-resolution genetic map, based on approximately 9,000 gametes and new molecular markers enabled us to delimit the GPC-B1 locus to a 7.4-kb region. Complete linkage of the 7.4-kb region with earlier senescence and increase in GPC, Zn, and Fe concentrations in the grain suggested that GPC-B1 is a single gene with multiple pleiotropic effects. The annotation of this 7.4-kb region identified a single gene, encoding a NAC transcription factor, designated as NAM-B1. Allelic variation studies demonstrated that the ancestral wild wheat allele encodes a functional NAC transcription factor whereas modern wheat varieties carry a non-functional NAM-B1 allele. Quantitative PCR showed that transcript levels for the multiple NAMhomologues were low in flag leaves prior to anthesis, after which their levels increased significantly towards grain maturity. Reduction in RNA levels of the multiple NAMhomologues by RNA interference delayed senescence by over three weeks and reduced wheat grain protein, Zn, and Fe content by over 30%. In the transgenic RNAi plants, residual N, Zn and Fe in the dry leaves was significantly higher than in the control plants, confirming a more efficient nutrient remobilization in the presence of higher levels of GPC. The multiple pleiotropic effects of NAM genes suggest a central role for these genes as transcriptional regulators of multiple processes during leaf senescence, including nutrient remobilization to the developing grain. The cloning of GPC-B1 provides a direct link between the regulation of senescence and nutrient remobilization and an entry point to characterize the genes regulating these two processes. This may contribute to their more efficient manipulation in crops and translate into food with enhanced nutritional value. The characterization of the GPC-B1 gene will have a significant impact on wheat production in many regions of the world and will open the door for the identification of additional genes involved in the accumulation of protein in the grain.
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Tucker, Mark L., Shimon Meir, Amnon Lers, Sonia Philosoph-Hadas, and Cai-Zhong Jiang. Elucidation of signaling pathways that regulate ethylene-induced leaf and flower abscission of agriculturally important plants. United States Department of Agriculture, January 2012. http://dx.doi.org/10.32747/2012.7597929.bard.
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The Problem: Abscission is a highly regulated process, occurring as a natural terminal stage of development, in which various organs are separated from the parent plant. In most plant species, the process is initiated by a decrease in active auxin in the abscission zone (AZ) and an increase in ethylene, and may be accelerated by postharvest or environmental stresses. Another potential key regulator in abscission is IDA (Inflorescence Deficient in Abscission), which was identified as an essential peptide signal for floral organ abscission in Arabidopsis. However, information is still lacking regarding the molecular mechanisms integrating all these regulators. In our previous BARD funded research we made substantial progress towards understanding these molecular events in tomato, and the study is still in progress. We established a powerful platform for analysis of genes for regulatory proteins expressed in AZ. We identified changes in gene expression for several transcription factors (TFs) directly linked to ethylene and auxin signaling and several additional regulatory proteins not so obviously linked to these hormones. Moreover, we demonstrated using a virus-induced gene silencing (VIGS) assay that several play a functional role in the onset of abscission. Based on these results we have selected 14 genes for further analysis in stably transformed tomato plants. All 14 genes were suppressed by RNA interference (RNAi) using a constitutive promoter, and 5 of them were also suppressed using an abscission-specific promoter. Transformations are currently at different stages of progress including some lines that already display an abscission phenotype. Objectives: We propose here to (1) complete the functional analysis of the stably transformed tomato plants with T2 lines and perform transcriptome analysis using custom abscission-specific microarrays; (2) conduct an indepth analysis of the role of IDA signaling in tomato leaf and flower abscission; (3) perform transcriptome and proteome analyses to extend the earlier gene expression studies to identify transcripts and proteins that are highly specific to the separation layer (i.e., target cells for cell separation) prior to the onset of abscission; (4) extend and compliment the work in tomato using a winnowed set of genes in soybean. Methodology: Next Generation Sequencing (NGS) of mRNA will be used to further increase the list of abscission-associated genes, and for preparation of a custom tomato abscission microarray to test altered gene expression in transgenic plants. Tandem mass spectrometry (LC-MS/MS) of protein extracts from leaf petiole, flower pedicel and their AZ tissues will be used to identify the proteome of the AZ before and during abscission. AZ-specific gene promoters will be used in stably transformed tomato plants to reduce non-target phenotypes. The bean pod mottle virus (BPMV) plasmid vectors will be used for VIGS analysis in soybean. Expected Contribution: Our study will provide new insights into the regulation of ethylene-induced abscission by further revealing the role of key regulators in the process. This will permit development of novel techniques for manipulating leaf and flower abscission, thereby improving the postharvest performance of agriculturally important crops.