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1
Wang, Yaolai, Jiaming Qi, Jie Shao, and Xu-Qing Tang. "Signaling Mechanism of Transcriptional Bursting: A Technical Resolution-Independent Study." Biology 9, no. 10 (October 19, 2020): 339. http://dx.doi.org/10.3390/biology9100339.
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Gene transcription has been uncovered to occur in sporadic bursts. However, due to technical difficulties in differentiating individual transcription initiation events, it remains debated as to whether the burst size, frequency, or both are subject to modulation by transcriptional activators. Here, to bypass technical constraints, we addressed this issue by introducing two independent theoretical methods including analytical research based on the classic two-model and information entropy research based on the architecture of transcription apparatus. Both methods connect the signaling mechanism of transcriptional bursting to the characteristics of transcriptional uncertainty (i.e., the differences in transcriptional levels of the same genes that are equally activated). By comparing the theoretical predictions with abundant experimental data collected from published papers, the results exclusively support frequency modulation. To further validate this conclusion, we showed that the data that appeared to support size modulation essentially supported frequency modulation taking into account the existence of burst clusters. This work provides a unified scheme that reconciles the debate on burst signaling.
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Nishimura, Akiko, Takeshi Ono, Akinori Ishimoto, Jennifer J. Dowhanick, Margaret A. Frizzell, Peter M. Howley, and Hiroyuki Sakai. "Mechanisms of Human Papillomavirus E2-Mediated Repression of Viral Oncogene Expression and Cervical Cancer Cell Growth Inhibition." Journal of Virology 74, no. 8 (April 15, 2000): 3752–60. http://dx.doi.org/10.1128/jvi.74.8.3752-3760.2000.
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ABSTRACT The papillomavirus E2 gene product plays a pivotal role in viral replication. E2 has multiple functions, including (i) transcriptional activation and repression of viral promoters and (ii) the enhancement of viral DNA replication. It was previously reported that E2 suppressed the growth of papillomavirus-positive cervical carcinoma cell lines. In the present study, we investigated the mechanisms of E2 growth inhibition. We found that the transcriptional activation function of E2 is required for inhibition of the growth of HeLa cells as well as for transcriptional repression of the viralE6/E7 promoter. It had been previously postulated that transcriptional repression of the E6/E7 promoter results from E2 binding its cognate sites proximal to the E6/E7promoter and displacing other cellular transcriptional factors. In this study, we report a requirement for the transcription activation function for the binding of E2 to transcriptionally active templates.
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Babu, M. Madan. "Computational approaches to study transcriptional regulation." Biochemical Society Transactions 36, no. 4 (July 22, 2008): 758–65. http://dx.doi.org/10.1042/bst0360758.
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In recent years, a number of technical and experimental advances have allowed us to obtain an unprecedented amount of information about living systems on a genomic scale. Although the complete genomes of many organisms are available due to the progress made in sequencing technology, the challenge to understand how the individual genes are regulated within the cell remains. Here, I provide an overview of current computational methods to investigate transcriptional regulation. I will first discuss how representing protein–DNA interactions as a network provides us with a conceptual framework to understand the organization of regulatory interactions in an organism. I will then describe methods to predict transcription factors and cis-regulatory elements using information such as sequence, structure and evolutionary conservation. Finally, I will discuss approaches to infer genome-scale transcriptional regulatory networks using experimentally characterized interactions from model organisms and by reverse-engineering regulatory interactions that makes use of gene expression data and genomewide location data. The methods summarized here can be exploited to discover previously uncharacterized transcriptional pathways in organisms whose genome sequence is known. In addition, such a framework and approach can be invaluable to investigate transcriptional regulation in complex microbial communities such as the human gut flora or populations of emerging pathogens. Apart from these medical applications, the concepts and methods discussed can be used to understand the combinatorial logic of transcriptional regulation and can be exploited in biotechnological applications, such as in synthetic biology experiments aimed at engineering regulatory circuits for various purposes.
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Bouget, François-Yves, Marc Lefranc, Quentin Thommen, Benjamin Pfeuty, Jean-Claude Lozano, Philippe Schatt, Hugo Botebol, and Valérie Vergé. "Transcriptional versus non-transcriptional clocks: A case study in Ostreococcus." Marine Genomics 14 (April 2014): 17–22. http://dx.doi.org/10.1016/j.margen.2014.01.004.
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Rossi, Alessandra, Ilenia Pacella, and Silvia Piconese. "RNA Flow Cytometry for the Study of T Cell Metabolism." International Journal of Molecular Sciences 22, no. 8 (April 9, 2021): 3906. http://dx.doi.org/10.3390/ijms22083906.
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T cells undergo activation and differentiation programs along a continuum of states that can be tracked through flow cytometry using a combination of surface and intracellular markers. Such dynamic behavior is the result of transcriptional and post-transcriptional events, initiated and sustained by the activation of specific transcription factors and by epigenetic remodeling. These signaling pathways are tightly integrated with metabolic routes in a bidirectional manner: on the one hand, T cell receptors and costimulatory molecules activate metabolic reprogramming; on the other hand, metabolites modify T cell transcriptional programs and functions. Flow cytometry represents an invaluable tool to analyze the integration of phenotypical, functional, metabolic and transcriptional features, at the single cell level in heterogeneous T cell populations, and from complex microenvironments, with potential clinical application in monitoring the efficacy of cancer immunotherapy. Here, we review the most recent advances in flow cytometry-based analysis of gene expression, in combination with indicators of mitochondrial activity, with the aim of revealing and characterizing major metabolic pathways in T cells.
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SINHA, Anupama, Douglas V. FALLER, and Gerald V. DENIS. "Bromodomain analysis of Brd2-dependent transcriptional activation of cyclin A1." Biochemical Journal 387, no. 1 (March 22, 2005): 257–69. http://dx.doi.org/10.1042/bj20041793.
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Cyclin A is regulated primarily through transcription control during the mammalian cell cycle. A dual mechanism of cyclin A transcriptional repression involves, on the one hand, promoter-bound inhibitory complexes of E2F transcription factors and RB (retinoblastoma) family proteins, and on the other, chromatin-directed histone deacetylase activity that is recruited to the cyclin A promoter early in the cell cycle in association with these RB proteins. This dual regulation maintains transcriptional silence of the cyclin A locus until its transcription is required in S-phase. At that time, RB family members dissociate from E2F proteins and nucleosomal restructuring of the locus takes place, to permit transcriptional activation and resultant S-phase progression to proceed. We have identified a double bromo-domain-containing protein Brd2, which exhibits apparent ‘scaffold’ or transcriptional adapter functions and mediates recruitment of both E2F transcription factors and chromatin-remodelling activity to the cyclin A promoter. We have shown previously that Brd2-containing nuclear, multiprotein complexes contain E2F-1 and -2. In the present study, we show that, in S-phase, they also contain histone H4-directed acetylase activity. Overexpression of Brd2 in fibroblasts accelerates the cell cycle through increased expression of cyclin A and its associated cyclin-dependent kinase activity. Chromatin immunoprecipitation studies show that Brd2 is physically present at the cyclin A promoter and its overexpression promotes increased histone H4 acetylation at the promoter as it becomes transcriptionally active, suggesting a new model for the dual regulation of cyclin A.
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Cipolletti, Manuela, Sara Pescatori, and Filippo Acconcia. "Real-Time Challenging of ERα Y537S Mutant Transcriptional Activity in Living Cells." Endocrines 2, no. 1 (March 10, 2021): 54–64. http://dx.doi.org/10.3390/endocrines2010006.
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Metastatic estrogen receptor α (ERα)-expressing breast cancer (BC) occurs after prolonged patient treatment with endocrine therapy (ET) (e.g., aromatase inhibitors—AI; 4OH-tamoxifen—4OH-Tam). Often these metastatic BCs express a mutated ERα variant (e.g., Y537S), which is transcriptionally hyperactive, sustains uncontrolled proliferation, and renders tumor cells insensitive to ET drugs. Therefore, new molecules blocking hyperactive Y537S ERα mutation transcriptional activity are requested. Here we generated an MCF-7 cell line expressing the Y537S ERα mutation stably expressing an estrogen-responsive element (ERE) promoter, which activity can be monitored in living cells. Characterization of this cell line shows both hyperactive basal transcriptional activity with respect to normal MCF-7 cells, which stably express the same ERE-based promoter and a decreased effect of selective ER downregulators (SERDs) in reducing Y537S ERα mutant transcriptional activity with respect to wild type ERα transcriptional activity. Kinetic profiles of Y537S ERα mutant-based transcription produced by both drugs inducing receptor degradation and siRNA-mediated depletion of specific proteins (e.g., FOXA1 and caveolin1) reveals biphasic dynamics of the inhibition of the receptor-regulated transcriptional effects. Overall, we report a new model where to study the behavior of the Y537S ERα mutant that can be used for the identification of new targets and pathways regulating the Y537S ERα transcriptional activity.
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Teves, Sheila S., and Steven Henikoff. "The heat shock response: A case study of chromatin dynamics in gene regulation." Biochemistry and Cell Biology 91, no. 1 (February 2013): 42–48. http://dx.doi.org/10.1139/bcb-2012-0075.
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Recent studies in transcriptional regulation using the Drosophila heat shock response system have elucidated many of the dynamic regulatory processes that govern transcriptional activation and repression. The classic view that the control of gene expression occurs at the point of RNA polymerase II (Pol II) recruitment is now giving way to a more complex outlook of gene regulation. Promoter chromatin dynamics coordinate with transcription factor binding to maintain the promoters of active genes accessible. For a large number of genes, the rate-limiting step in Pol II progression occurs during its initial elongation, where Pol II transcribes 30–50 bp and pauses for further signals. These paused genes have unique genic chromatin architecture and dynamics compared with genes where Pol II recruitment is rate limiting for expression. Further elongation of Pol II along the gene causes nucleosome turnover, a continuous process of eviction and replacement, which suggests a potential mechanism for Pol II transit along a nucleosomal template. In this review, we highlight recent insights into transcription regulation of the heat shock response and discuss how the dynamic regulatory processes involved at each transcriptional stage help to generate faithful yet highly responsive gene expression.
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ARAO, Yukitomo, Etsuko YAMAMOTO, Naoto MIYATAKE, Yuichi NINOMIYA, Taisuke UMEHARA, Hiroyuki KAWASHIMA, Shoichi MASUSHIGE, Tadao HASEGAWA, and Shigeaki KATO. "A synthetic oestrogen antagonist, tamoxifen, inhibits oestrogen-induced transcriptional, but not post-transcriptional, regulation of gene expression." Biochemical Journal 313, no. 1 (January 1, 1996): 269–74. http://dx.doi.org/10.1042/bj3130269.
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Oestrogen (E2) regulates the expression of its target genes at transcriptional and post-transcriptional levels. To clarify the mechanism of E2-induced post-transcriptional regulation, with attention to the involvement of the oestrogen receptor (ER), we studied the effect of tamoxifen (TAM), a synthetic E2 antagonist that inhibits ER-mediated transcription, on E2-induced transcriptional and post-transcriptional regulation of the chicken ovalbumin (OVA) gene in chick oviducts. Run-on analysis with oviduct nuclei isolated from E2-treated chicks showed that TAM treatment completely blocked E2-induced transcription of the OVA gene within 24 h without affecting ER gene expression. Likewise, the rate of transcription fell to below the limit of detection after E2 withdrawal from the chicks. Reflecting the transcription rate, OVA mRNA accumulated linearly in E2-treated chicks, and E2 withdrawal caused a rapid loss of OVA mRNA. However, in the chicks treated with TAM and E2, OVA mRNA was degraded slowly over 48 h with a half-life of 24 h, suggesting that TAM does not inhibit E2-induced mRNA stabilization. Moreover, E2-induced mRNA stabilization was observed even when transcription of the OVA gene was blocked by a transcription inhibitor. Western-blot analysis showed that the remaining OVA mRNA was translatable. Thus the present study indicates that E2 regulates expression of the OVA gene via distinct pathways at transcriptional and post-transcriptional levels.
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Sadka, Avi, Qiaoping Qin, Jianrong Feng, Macarena Farcuh, Lyudmila Shlizerman, Yunting Zhang, David Toubiana, and Eduardo Blumwald. "Ethylene Response of Plum ACC Synthase 1 (ACS1) Promoter is Mediated through the Binding Site of Abscisic Acid Insensitive 5 (ABI5)." Plants 8, no. 5 (May 2, 2019): 117. http://dx.doi.org/10.3390/plants8050117.
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The enzyme 1-amino-cyclopropane-1-carboxylic acid synthase (ACS) participates in the ethylene biosynthesis pathways and it is tightly regulated transcriptionally and post-translationally. Notwithstanding its major role in climacteric fruit ripening, the transcriptional regulation of ACS during ripening is not fully understood. We studied fruit ripening in two Japanese plum cultivars, the climacteric Santa Rosa (SR) and its non-climacteric bud sport mutant, Sweet Miriam (SM). As the two cultivars show considerable difference in ACS expression, they provide a good system for the study of the transcriptional regulation of the gene. To investigate the differential transcriptional regulation of ACS1 genes in the SR and SM, their promoter regions, which showed only minor sequence differences, were isolated and used to identify the binding of transcription factors interacting with specific ACS1 cis-acting elements. Three transcription factors (TFs), abscisic acid-insensitive 5 (ABI5), GLABRA 2 (GL2), and TCP2, showed specific binding to the ACS1 promoter. Synthetic DNA fragments containing multiple cis-acting elements of these TFs fused to β-glucuronidase (GUS), showed the ABI5 binding site mediated ethylene and abscisic acid (ABA) responses of the promoter. While TCP2 and GL2 showed constant and similar expression levels in SM and SR fruit during ripening, ABI5 expression in SM fruits was lower than in SR fruits during advanced fruit ripening states. Overall, the work demonstrates the complex transcriptional regulation of ACS1.
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Mobley, Constance M., and Linda Sealy. "Role of the Transcription Start Site Core Region and Transcription Factor YY1 in Rous Sarcoma Virus Long Terminal Repeat Promoter Activity." Journal of Virology 72, no. 8 (August 1, 1998): 6592–601. http://dx.doi.org/10.1128/jvi.72.8.6592-6601.1998.
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ABSTRACT The Rous sarcoma virus (RSV) long terminal repeat (LTR) contains a transcriptionally potent enhancer and promoter that functions in a variety of cell types. Previous studies have identified the viral sequences required for enhancer activity, and characterization of these elements has provided insight into the mechanism of RSV transcriptional activity. The objective of this study was to better define the RSV LTR promoter by examining the transcription start site core (TSSC) region. Deletion of the TSSC resulted in complete loss of transcriptional activity despite the presence of a functional TATA box, suggesting that the TSSC is required for viral expression. Homologies within the TSSC to the DNA binding motif of YY1 suggested that it might regulate promoter activity. YY1 has been shown to regulate transcription in some cellular genes and viral promoters by binding to sites overlapping the transcription start site. Gel shift assays using YY1 antibody identified YY1 as one of three complexes that bound to the TSSC. Mutation of the YY1 binding site reduced RSV transcriptional activity by more than 50%, suggesting that YY1, in addition to other TSSC-binding factors, regulates RSV transcription. Furthermore, in vitro transcription assays performed with Drosophila embryo extract (devoid of YY1 activity) showed decreased levels of RSV transcription, while transient transfection experiments overexpressing YY1 demonstrated that YY1 could transactivate the RSV LTR ∼6- to 7-fold. We propose that the TSSC plays a vital role in RSV transcription and that this function is partially carried out by the transcription factor YY1.
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Cattoglio, Claudia, Elisa T. Zhang, Ivan Grubisic, Kunitoshi Chiba, Yick W. Fong, and Robert Tjian. "Functional and mechanistic studies of XPC DNA-repair complex as transcriptional coactivator in embryonic stem cells." Proceedings of the National Academy of Sciences 112, no. 18 (April 21, 2015): E2317—E2326. http://dx.doi.org/10.1073/pnas.1505569112.
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The embryonic stem cell (ESC) state is transcriptionally controlled by OCT4, SOX2, and NANOG with cofactors, chromatin regulators, noncoding RNAs, and other effectors of signaling pathways. Uncovering components of these regulatory circuits and their interplay provides the knowledge base to deploy ESCs and induced pluripotent stem cells. We recently identified the DNA-repair complex xeroderma pigmentosum C (XPC)-RAD23B-CETN2 as a stem cell coactivator (SCC) required for OCT4/SOX2 transcriptional activation. Here we investigate the role of SCC genome-wide in murine ESCs by mapping regions bound by RAD23B and analyzing transcriptional profiles of SCC-depleted ESCs. We establish OCT4 and SOX2 as the primary transcription factors recruiting SCC to regulatory regions of pluripotency genes and identify the XPC subunit as essential for interaction with the two proteins. The present study reveals new mechanistic and functional aspects of SCC transcriptional activity, and thus underscores the diversified functions of this regulatory complex.
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Buist, Marjorie, David Fuss, and Mojgan Rastegar. "Transcriptional Regulation of MECP2E1-E2 Isoforms and BDNF by Metformin and Simvastatin through Analyzing Nascent RNA Synthesis in a Human Brain Cell Line." Biomolecules 11, no. 8 (August 22, 2021): 1253. http://dx.doi.org/10.3390/biom11081253.
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Methyl CpG binding protein 2 (MeCP2) is the main DNA methyl-binding protein in the brain that binds to 5-methylcytosine and 5-hydroxymethyl cytosine. MECP2 gene mutations are the main origin of Rett Syndrome (RTT), a neurodevelopmental disorder in young females. The disease has no existing cure, however, metabolic drugs such as metformin and statins have recently emerged as potential therapeutic candidates. In addition, induced MECP2-BDNF homeostasis regulation has been suggested as a therapy avenue. Here, we analyzed nascent RNA synthesis versus steady state total cellular RNA to study the transcriptional effects of metformin (an anti-diabetic drug) on MECP2 isoforms (E1 and E2) and BNDF in a human brain cell line. Additionally, we investigated the impact of simvastatin (a cholesterol lowering drug) on transcriptional regulation of MECP2E1/E2-BDNF. Metformin was capable of post-transcriptionally inducing BDNF and/or MECP2E1, while transcriptionally inhibiting MECP2E2. In contrast simvastatin significantly inhibited BDNF transcription without significantly impacting MECP2E2 transcripts. Further analysis of ribosomal RNA transcripts confirmed that the drug neither individually nor in combination affected these fundamentally important transcripts. Experimental analysis was completed in conditions of the presence or absence of serum starvation that showed minimal impact for serum deprival, although significant inhibition of steady state MECP2E1 by simvastatin was only detected in non-serum starved cells. Taken together, our results suggest that metformin controls MECP2E1/E2-BDNF transcriptionally and/or post-transcriptionally, and that simvastatin is a potent transcriptional inhibitor of BDNF. The transcriptional effect of these drugs on MECP2E1/E2-BDNF were not additive under these tested conditions, however, either drug may have potential application for related disorders.
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Harada, Taku, Yaser Heshmati, Jérémie Kalfon, Monika W. Perez, Juliana Xavier Ferrucio, Jazmin Ewers, Benjamin Hubbell Engler, et al. "A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia." Genes & Development 36, no. 5-6 (March 1, 2022): 368–89. http://dx.doi.org/10.1101/gad.349284.121.
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Acute myeloid leukemia with KMT2A (MLL) rearrangements is characterized by specific patterns of gene expression and enhancer architecture, implying unique core transcriptional regulatory circuitry. Here, we identified the transcription factors MEF2D and IRF8 as selective transcriptional dependencies of KMT2A-rearranged AML, where MEF2D displays partially redundant functions with its paralog, MEF2C. Rapid transcription factor degradation followed by measurements of genome-wide transcription rates and superresolution microscopy revealed that MEF2D and IRF8 form a distinct core regulatory module with a narrow direct transcriptional program that includes activation of the key oncogenes MYC, HOXA9, and BCL2. Our study illustrates a mechanism of context-specific transcriptional addiction whereby a specific AML subclass depends on a highly specialized core regulatory module to directly enforce expression of common leukemia oncogenes.
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Neely, Lori A., and Charles S. Hoffman. "Protein Kinase A and Mitogen-Activated Protein Kinase Pathways Antagonistically Regulate Fission Yeast fbp1Transcription by Employing Different Modes of Action at Two Upstream Activation Sites." Molecular and Cellular Biology 20, no. 17 (September 1, 2000): 6426–34. http://dx.doi.org/10.1128/mcb.20.17.6426-6434.2000.
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ABSTRACT A significant challenge to our understanding of eukaryotic transcriptional regulation is to determine how multiple signal transduction pathways converge on a single promoter to regulate transcription in divergent fashions. To study this, we have investigated the transcriptional regulation of theSchizosaccharomyces pombe fbp1 gene that is repressed by a cyclic AMP (cAMP)-dependent protein kinase A (PKA) pathway and is activated by a stress-activated mitogen-activated protein kinase (MAPK) pathway. In this study, we identified and characterized twocis-acting elements in the fbp1 promoter required for activation of fbp1 transcription. Upstream activation site 1 (UAS1), located approximately 900 bp from the transcriptional start site, resembles a cAMP response element (CRE) that is the binding site for the atf1-pcr1 heterodimeric transcriptional activator. Binding of this activator to UAS1 is positively regulated by the MAPK pathway and negatively regulated by PKA. UAS2, located approximately 250 bp from the transcriptional start site, resembles a Saccharomyces cerevisiae stress response element. UAS2 is bound by transcriptional activators and repressors regulated by both the PKA and MAPK pathways, although atf1 itself is not present in these complexes. Transcriptional regulation offbp1 promoter constructs containing only UAS1 or UAS2 confirms that the PKA and MAPK regulation is targeted to both sites. We conclude that the PKA and MAPK signal transduction pathways regulatefbp1 transcription at UAS1 and UAS2, but that the antagonistic interactions between these pathways involve different mechanisms at each site.
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Topalidou, Irini, Manolis Papamichos-Chronakis, and George Thireos. "Post-TATA Binding Protein Recruitment Clearance of Gcn5-Dependent Histone Acetylation within Promoter Nucleosomes." Molecular and Cellular Biology 23, no. 21 (November 1, 2003): 7809–17. http://dx.doi.org/10.1128/mcb.23.21.7809-7817.2003.
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ABSTRACT Transcriptional activation of eukaryotic genes often requires the function of histone acetyltransferases (HATs), which is expected to result in the hyperacetylation of histones within promoter nucleosomes. In this study we show that, in Saccharomyces cerevisiae, the steady-state levels of Gcn5-dependent histone acetylation within a number of transcriptionally active promoters are inversely related to the rate of transcription. High acetylation levels were measured only when transcription was attenuated either by TATA element mutations or in a strain carrying a temperature-sensitive protein component of RNA polymerase II. In addition, we show that in one case the low levels of histone acetylation depend on the function of the Rpd3 histone deacetylase. These results point to the existence of an unexpected interplay of two opposing histone-modifying activities which operate on promoter nucleosomes following the initiation of RNA synthesis. Such interplay could ensure rapid turnover of chromatin acetylation states in continuously reprogrammed transcriptional systems.
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Ochiai, Hiroshi, Tetsutaro Hayashi, Mana Umeda, Mika Yoshimura, Akihito Harada, Yukiko Shimizu, Kenta Nakano, et al. "Genome-wide kinetic properties of transcriptional bursting in mouse embryonic stem cells." Science Advances 6, no. 25 (June 2020): eaaz6699. http://dx.doi.org/10.1126/sciadv.aaz6699.
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Transcriptional bursting is the stochastic activation and inactivation of promoters, contributing to cell-to-cell heterogeneity in gene expression. However, the mechanism underlying the regulation of transcriptional bursting kinetics (burst size and frequency) in mammalian cells remains elusive. In this study, we performed single-cell RNA sequencing to analyze the intrinsic noise and mRNA levels for elucidating the transcriptional bursting kinetics in mouse embryonic stem cells. Informatics analyses and functional assays revealed that transcriptional bursting kinetics was regulated by a combination of promoter- and gene body–binding proteins, including the polycomb repressive complex 2 and transcription elongation factors. Furthermore, large-scale CRISPR-Cas9–based screening identified that the Akt/MAPK signaling pathway regulated bursting kinetics by modulating transcription elongation efficiency. These results uncovered the key molecular mechanisms underlying transcriptional bursting and cell-to-cell gene expression noise in mammalian cells.
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Bergallo, Massimiliano, Ilaria Galliano, Valentina Daprà, Alice Pirra, Paola Montanari, Marzia Pavan, Cristina Calvi, Enrico Bertino, Alessandra Coscia, and Pier-Angelo Tovo. "Transcriptional Activity of Human Endogenous Retroviruses in Response to Prenatal Exposure of Maternal Cigarette Smoking." American Journal of Perinatology 36, no. 10 (November 30, 2018): 1060–65. http://dx.doi.org/10.1055/s-0038-1675768.
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Objective Transcription of human endogenous retrovirus (HERV) elements is usually suppressed by epigenetic factors such as DNA methylation and heterochromatin silencing by histone modifications. There is an association between maternal smoking during pregnancy and DNA methylation levels in placental tissue and in DNA from cord blood. Study Design We assessed the transcriptional activity of HERV-H, HERV-K, and HERV-W in umbilical cord blood from 47 term babies unexposed to tobacco smoke in utero and 23 term babies exposed to tobacco smoke in utero. Results In our population, the HERV-H, HERV-K, and HERV-W families were always transcriptionally active, and the levels of all HERVs (H, K, W) were significantly higher in unexposed than smoke-exposed babies. Conclusion This study provides preliminary information about the transcriptional activity of HERV-H, HERV-K, and HERV-W families in human umbilical cord blood.
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Konietzko, Uwe, Manuel T. Gersbacher, Jeremy Streuli, Maik Krüger, Sarina Thöni, Stefan Kins, and Roger M. Nitsch. "A fluorescent protein-readout for transcriptional activity reveals regulation of APP nuclear signaling by phosphorylation sites." Biological Chemistry 400, no. 9 (August 27, 2019): 1191–203. http://dx.doi.org/10.1515/hsz-2019-0125.
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Abstract Signaling pathways that originate at the plasma membrane, including regulated intramembrane proteolysis (RIP), enable extracellular cues to control transcription. We modified the yeast Gal4 transcription system to study the nuclear translocation of transcriptionally active complexes using the fluorescent protein citrine (Cit) as a reporter. This enabled highly sensitive quantitative analysis of transcription in situ at the single cell level. The Gal4/UAS-Cit transcription assay displayed a sigmoidal response limited by the number of integrated reporter cassettes. We validated the assay by analyzing nuclear translocation of the amyloid precursor protein (APP) intracellular domain (AICD) and confirmed the requirement of Fe65 for nuclear translocation of AICD. In addition to the strong on-off effects on transcriptional activity, the results of this assay establish that phosphorylation modifies nuclear signaling. The Y682F mutation in APP showed the strongest increase in Cit expression, underscoring its role in regulating Fe65 binding. Together, we established a highly sensitive fluorescent protein-based assay that can monitor transcriptional activity at the single cell level and demonstrate that AICD phosphorylation affects Fe65 nuclear activity. This assay also introduces a platform for future single cell-based drug screening methods for nuclear translocation.
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Wang, Jianrong, and Andrew Yen. "A Novel Retinoic Acid-Responsive Element Regulates Retinoic Acid-Induced BLR1 Expression." Molecular and Cellular Biology 24, no. 6 (March 15, 2004): 2423–43. http://dx.doi.org/10.1128/mcb.24.6.2423-2443.2004.
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ABSTRACT The mechanism of action of retinoic acid (RA) is of broad relevance to cell and developmental biology, nutrition, and cancer chemotherapy. RA is known to induce expression of the Burkitt's lymphoma receptor 1 (BLR1) gene which propels RA-induced cell cycle arrest and differentiation of HL-60 human myeloblastic leukemia cells, motivating the present analysis of transcriptional regulation of blr1 expression by RA. The RA-treated HL-60 cells used here expressed all RA receptor (RAR) and retinoid X receptor (RXR) subtypes (as detected by Northern analysis) except RXRγ. Treatment with RAR- and RXR-selective ligands showed that RARα synergized with RXRα to transcriptionally activate blr1 expression. A 5′-flanking region capable of supporting RA-induced blr1 activation in HL-60 cells was found to contain a 205-bp sequence in the distal portion that was necessary for transcriptional activation by RA. Within this sequence DNase I footprinting revealed that RA induced binding of a nuclear protein complex to an element containing two GT boxes. Electromobility shift assays (EMSAs) and supershift assays showed that this element bound recombinant RARα and RXRα. Without RA there was neither complex binding nor transcriptional activation. Both GT boxes were needed for binding the complex, and mutation of either GT box caused the loss of transcriptional activation by RA. The ability of this cis-acting RAR-RXR binding element to activate transcription in response to RA also depended on downstream sequences where an octamer transcription factor 1 (Oct1) site and a nuclear factor of activated T cells (NFATc) site between this element and the transcriptional start, as well as a cyclic AMP response element binding factor (CREB) site between the transcriptional start and first exon of the blr1 gene, were necessary. Each of these sites bound its corresponding transcription factor. A transcription factor-transcription factor binding array analysis of nuclear lysate from RA-treated cells indicated several prominent RARα binding partners; among these, Oct1, NFATc3, and CREB2 were identified by competition EMSA and supershift and chromatin immunoprecipitation assays as components of the complex. RA upregulated expression of these three factors. In sum the results of the present study indicate that RA-induced expression of blr1 expression depends on a novel RA response element. This cis-acting element approximately 1 kb upstream of the transcriptional start consists of two GT boxes that bind RAR and RXR in a nuclear protein complex that also contains Oct1, NFATc3, and CREB2 bound to their cognate downstream consensus binding sites.
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Hwang, Jacqueline R., Chung-Lin Chou, Barbara Medvar, Mark A. Knepper, and Hyun Jun Jung. "Identification of β-catenin-interacting proteins in nuclear fractions of native rat collecting duct cells." American Journal of Physiology-Renal Physiology 313, no. 1 (July 1, 2017): F30—F46. http://dx.doi.org/10.1152/ajprenal.00054.2017.
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The gene encoding the aquaporin-2 water channel is regulated transcriptionally in response to vasopressin. In the renal collecting duct, vasopressin stimulates the nuclear translocation and phosphorylation (at Ser552) of β-catenin, a multifunctional protein that acts as a transcriptional coregulator in the nucleus. The purpose of this study was to identify β-catenin-interacting proteins that might be involved in transcriptional regulation in rat inner medullary collecting duct (IMCD) cells, using experimental and computational approaches. We used a standard chromatin immunoprecipitation procedure coupled to mass spectrometry (ChIP-MS) in a nuclear fraction isolated from rat IMCD suspensions. Over four biological replicates, we reproducibly identified 43 β-catenin-binding proteins, including several known β-catenin-binding partners as well as novel interacting proteins. Multiple proteins involved in transcriptional regulation were identified (Taf1, Jup, Tdrd3, Cdh1, Cenpj, and several histones). Many of the identified β-catenin-binding partners were found in prior studies to translocate to the nucleus in response to vasopressin. There was only one DNA-binding transcription factor (TF), specifically Taf1, part of the RNA-polymerase II preinitiation complex. To identify sequence-specific TFs that might interact with β-catenin, Bayes’ theorem was used to integrate data from several information sources. The analysis identified several TFs with potential binding sites in the Aqp2 gene promoter that could interact with β-catenin in the regulation of Aqp2 gene transcription, specifically Jun, Junb, Jund, Atf1, Atf2, Mef2d, Usf1, Max, Pou2f1, and Rxra. The findings provide information necessary for modeling the transcriptional response to vasopressin.
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Haase, S. B., S. S. Heinzel, and M. P. Calos. "Transcription inhibits the replication of autonomously replicating plasmids in human cells." Molecular and Cellular Biology 14, no. 4 (April 1994): 2516–24. http://dx.doi.org/10.1128/mcb.14.4.2516.
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This study addresses the effect of transcription on replication, using a system based on autonomously replicating plasmids in human cells. We added transcriptional elements from the human cytomegalovirus promoter/enhancer and the human beta-actin promoter to autonomously replicating plasmids based on human sequences and found that the transcriptional elements inhibited plasmid replication. Furthermore, conditional inhibition of plasmid replication was demonstrated by using a tetracycline-responsive promoter. We found that replication activity of plasmids carrying this promoter was inversely correlated with promoter activity. Replication activity was partially restored on plasmids when a transcriptional termination sequence was placed directly downstream of the promoter element. Transcriptional activity of the promoters and the efficacy of the terminator sequence were confirmed by using steady-state RNA analysis. These experiments suggest that transcription inhibits DNA replication on these plasmids and that the degree of inhibition is dependent on transcription strength. The possible significance of these results for chromosomal DNA replication are discussed.
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Haase, S. B., S. S. Heinzel, and M. P. Calos. "Transcription inhibits the replication of autonomously replicating plasmids in human cells." Molecular and Cellular Biology 14, no. 4 (April 1994): 2516–24. http://dx.doi.org/10.1128/mcb.14.4.2516-2524.1994.
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This study addresses the effect of transcription on replication, using a system based on autonomously replicating plasmids in human cells. We added transcriptional elements from the human cytomegalovirus promoter/enhancer and the human beta-actin promoter to autonomously replicating plasmids based on human sequences and found that the transcriptional elements inhibited plasmid replication. Furthermore, conditional inhibition of plasmid replication was demonstrated by using a tetracycline-responsive promoter. We found that replication activity of plasmids carrying this promoter was inversely correlated with promoter activity. Replication activity was partially restored on plasmids when a transcriptional termination sequence was placed directly downstream of the promoter element. Transcriptional activity of the promoters and the efficacy of the terminator sequence were confirmed by using steady-state RNA analysis. These experiments suggest that transcription inhibits DNA replication on these plasmids and that the degree of inhibition is dependent on transcription strength. The possible significance of these results for chromosomal DNA replication are discussed.
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Gao, Weixia, Xiaoliang Zhang, Guangtong Zhang, Meng Zuo, Wei Cao, Zhoujie Xie, and Hao Liu. "Is hyaluronic acid production transcriptionally regulated? A transcriptional repressor gene deletion study in Streptococcus zooepidemicus." Applied Microbiology and Biotechnology 105, no. 21-22 (October 18, 2021): 8495–504. http://dx.doi.org/10.1007/s00253-021-11481-x.
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Sutherland, Greg T., Nicholas A. Matigian, Alistair M. Chalk, Matthew J. Anderson, Peter A. Silburn, Alan Mackay-Sim, Christine A. Wells, and George D. Mellick. "A Cross-Study Transcriptional Analysis of Parkinson's Disease." PLoS ONE 4, no. 3 (March 23, 2009): e4955. http://dx.doi.org/10.1371/journal.pone.0004955.
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Rusconi, Sandro, Yvonne Severne, Oleg Georgiev, Ivo Galli, and Stefan Wieland. "A novel expression assay to study transcriptional activators." Gene 89, no. 2 (May 1990): 211–21. http://dx.doi.org/10.1016/0378-1119(90)90008-f.
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Jones, L., H. Richardson, and R. Saint. "Tissue-specific regulation of cyclin E transcription during Drosophila melanogaster embryogenesis." Development 127, no. 21 (November 1, 2000): 4619–30. http://dx.doi.org/10.1242/dev.127.21.4619.
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Cyclin E is an essential regulator of S phase entry. We have previously shown that transcriptional regulation of the gene that encodes Drosophila cyclin E, DmcycE, plays an important role in the control of the G(1) to S phase transition during development. We report here the first comprehensive analysis of the transcriptional regulation of a G(1)phase cell cycle regulatory gene during embryogenesis. Analysis of deficiencies, a genomic transformant and reporter gene constructs revealed that DmcycE transcription is controlled by a large and complex cis-regulatory region containing tissue- and stage-specific components. Separate regulatory elements for transcription in epidermal cells during cell cycles 14–16, central nervous system cells and peripheral nervous system cells were found. An additional cis-regulatory element drives transcription in thoracic epidermal cells that undergo a 17th cell cycle when other epidermal cells have arrested in G(1)phase prior to terminal differentiation. The complexity of DmcycE transcriptional regulation argues against a model in which DmcycE transcription is regulated simply and solely by G(1) to S phase transcription regulators such as RB, E2F and DP. Rather, our study demonstrates that tissue-specific transcriptional regulatory mechanisms are important components of the control of cyclin E transcription and thus of cell proliferation in metazoans.
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PEI, Lin. "Transcriptional repressor of vasoactive intestinal peptide receptor mediates repression through interactions with TFIIB and TFIIEβ." Biochemical Journal 360, no. 3 (December 10, 2001): 633–38. http://dx.doi.org/10.1042/bj3600633.
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The transcriptional repressor for rat vasoactive-intestinal-polypeptide receptor 1 (VIPR-RP) is a recently characterized transcription factor that belongs to a family of proteins, which include components of the DNA replication factor C complex. In this study, I investigated the mechanisms by which VIPR-RP represses transcription. I show here that transcriptional repression by VIPR-RP is mediated by a histone deacetylase-independent mechanism. I provide evidence that VIPR-RP makes direct physical contacts with two proteins of the basal transcription apparatus, the transcription factors TFIIB and TFIIEβ. The interaction with TFIIB is mediated by the N-terminal 180 amino acids, whereas the interactive domain with TFIIEβ is located between residues 367 and 527 of VIPR-RP. Using gel mobility-shift assays I demonstrated that interaction between VIPR-RP and TFIIB prevents the recruitment of TFIIB into a DNA–TATA-box-binding protein complex. My results indicate that VIPR-RP mediates transcriptional repression through direct interactions with the general transcription machinery.
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Uhm, Heesoo, Wooyoung Kang, Kook Sun Ha, Changwon Kang, and Sungchul Hohng. "Single-molecule FRET studies on the cotranscriptional folding of a thiamine pyrophosphate riboswitch." Proceedings of the National Academy of Sciences 115, no. 2 (December 26, 2017): 331–36. http://dx.doi.org/10.1073/pnas.1712983115.
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Because RNAs fold as they are being synthesized, their transcription rate can affect their folding. Here, we report the results of single-molecule fluorescence studies that characterize the ligand-dependent cotranscriptional folding of the Escherichia coli thiM riboswitch that regulates translation. We found that the riboswitch aptamer folds into the “off” conformation independent of its ligand, but switches to the “on” conformation during transcriptional pausing near the translational start codon. Ligand binding maintains the riboswitch in the off conformation during transcriptional pauses. We expect our assay will permit the controlled study of the two main physical mechanisms that regulate cotranscriptional folding: transcriptional pausing and transcriptional speed.
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Winnay, Jonathon N., and Gary D. Hammer. "Adrenocorticotropic Hormone-Mediated Signaling Cascades Coordinate a Cyclic Pattern of Steroidogenic Factor 1-Dependent Transcriptional Activation." Molecular Endocrinology 20, no. 1 (January 1, 2006): 147–66. http://dx.doi.org/10.1210/me.2005-0215.
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Abstract Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that has emerged as a critical mediator of endocrine function at multiple levels of the hypothalamic-pituitary-steroidogenic axis. Within the adrenal cortex, ACTH-dependent transcriptional responses, including transcriptional activation of several key steroidogenic enzymes within the steroid biosynthetic pathway, are largely dependent upon SF-1 action. The absence of a bona fide endogenous eukaryotic ligand for SF-1 suggests that signaling pathway activation downstream of the melanocortin 2 receptor (Mc2r) modulates this transcriptional response. We have used the chromatin immunoprecipitation assay to examine the temporal formation of ACTH-dependent transcription complexes on the Mc2r gene promoter. In parallel, ACTH-dependent signaling events were examined in an attempt to correlate transcriptional events with the upstream activation of signaling pathways. Our results demonstrate that ACTH-dependent signaling cascades modulate the temporal dynamics of SF-1-dependent complex assembly on the Mc2r promoter. Strikingly, the pattern of SF-1 recruitment and the subsequent attainment of active rounds of transcription support a kinetic model of SF-1 transcriptional activation, a model originally established in the context of ligand-dependent transcription by several classical nuclear hormone receptors. An assessment of the major ACTH-dependent signaling pathways highlights pivotal roles for the MAPK as well as the cAMP-dependent protein kinase A pathway in the entrainment of SF-1-mediated transcriptional events. In addition, the current study demonstrates that specific enzymatic activities are capable of regulating distinct facets of a highly ordered transcriptional response.
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Lopez, Alex B., Chuanping Wang, Charlie C. Huang, Ibrahim Yaman, Yi Li, Kaushik Chakravarty, Peter F. Johnson, et al. "A feedback transcriptional mechanism controls the level of the arginine/lysine transporter cat-1 during amino acid starvation." Biochemical Journal 402, no. 1 (January 25, 2007): 163–73. http://dx.doi.org/10.1042/bj20060941.
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The adaptive response to amino acid limitation in mammalian cells inhibits global protein synthesis and promotes the expression of proteins that protect cells from stress. The arginine/lysine transporter, cat-1, is induced during amino acid starvation by transcriptional and post-transcriptional mechanisms. It is shown in the present study that the transient induction of cat-1 transcription is regulated by the stress response pathway that involves phosphorylation of the translation initiation factor, eIF2 (eukaryotic initiation factor-2). This phosphorylation induces expression of the bZIP (basic leucine zipper protein) transcription factors C/EBP (CCAAT/enhancer-binding protein)-β and ATF (activating transcription factor) 4, which in turn induces ATF3. Transfection experiments in control and mutant cells, and chromatin immunoprecipitations showed that ATF4 activates, whereas ATF3 represses cat-1 transcription, via an AARE (amino acid response element), TGATGAAAC, in the first exon of the cat-1 gene, which functions both in the endogenous and in a heterologous promoter. ATF4 and C/EBPβ activated transcription when expressed in transfected cells and they bound as heterodimers to the AARE in vitro. The induction of transcription by ATF4 was inhibited by ATF3, which also bound to the AARE as a heterodimer with C/EBPβ. These results suggest that the transient increase in cat-1 transcription is due to transcriptional activation caused by ATF4 followed by transcriptional repression by ATF3 via a feedback mechanism.
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Kim, Hee-Dae, Han Kyoung Choe, Sooyoung Chung, Myungjin Kim, Jae Young Seong, Gi Hoon Son, and Kyungjin Kim. "Class-C SOX Transcription Factors Control GnRH Gene Expression via the Intronic Transcriptional Enhancer." Molecular Endocrinology 25, no. 7 (July 1, 2011): 1184–96. http://dx.doi.org/10.1210/me.2010-0332.
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Abstract GnRH is a pivotal hypothalamic neurohormone governing reproduction and sexual development. Because transcriptional regulation is crucial for the spatial and temporal expression of the GnRH gene, a region approximately 3.0 kb upstream of the mammalian GnRH promoter has been extensive studied. In the present study, we demonstrate a transcription-enhancer located in the first intron (intron A) region of the GnRH gene. This transcriptional enhancer harbors putative sex-determining region Y-related high-mobility-group box (SOX) family transcription factor-binding sites, which are well conserved across many mammalian species. The class-C SOX member proteins (SOX-C) (SOX4 and SOX11) specifically augment this transcriptional activation by binding to these SOX-binding sites. In accordance, SOX11 is highly enriched in immortalized GnRH-producing GT1-1 cells, and suppression of its expression significantly decreases GnRH gene expression as well as GnRH secretion. Chromatin immunoprecipitation shows that endogenous SOX-C factors recognize and bind to the intronic enhancer in GT1-1 cells and the hypothalamus. Accompanying immunohistochemical analysis demonstrates that SOX4 or SOX11 are highly expressed in the majority of hypothalamic GnRH neurons in adult mice. Taken together, these findings demonstrate that SOX-C transcription factors function as important transcriptional regulators of cell type-specific GnRH gene expression by acting on the intronic transcriptional enhancer.
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Xiao, Gaoping, Jianxin He, and Laurence G. Rahme. "Mutation analysis of the Pseudomonas aeruginosa mvfR and pqsABCDE gene promoters demonstrates complex quorum-sensing circuitry." Microbiology 152, no. 6 (June 1, 2006): 1679–86. http://dx.doi.org/10.1099/mic.0.28605-0.
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The LysR-type transcriptional regulator MvfR (PqsR) (multiple virulence factor regulator) plays a critical role in Pseudomonas aeruginosa pathogenicity via the transcriptional regulation of multiple quorum-sensing (QS)-regulated virulence factors. LasR activates full mvfR transcription, and MvfR subsequently activates pqsA–E expression. This study identifies and characterizes the key cis-regulatory elements through which mvfR and pqsA–E transcription is regulated in the highly virulent P. aeruginosa strain PA14. Deletion and site-directed mutagenesis indicate that: (1) LasR activates mvfR transcription by binding to a las/rhl box, CTAACAAAAGACATAG, centred at −513 bp upstream of the MvfR translational start site; and (2) RhlR represses pqsA transcription by binding to a las/rhl box, CTGTGAGATTTGGGAG, centred at −311 bp upstream of the pqsA transcriptional initiation site. Furthermore, it is shown that MvfR activates pqsA–E transcription by binding to a LysR box, TTCGGACTCCGAA, centred at −45 bp relative to the pqsA transcriptional initiation site, demonstrating that this LysR box has a critical role in the physical interaction between the MvfR protein and the pqsA promoter. These results provide new insights into the regulatory relationships between LasR and mvfR, and between MvfR/RhlR and the pqs operon, and elucidate further the complex regulation of the P. aeruginosa QS circuitry.
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Rhee, Jinseol, Je-Hwang Ryu, Jin-Hong Kim, Churl-Hong Chun, and Jang-Soo Chun. "α-Catenin Inhibits β-Catenin-T-cell Factor/Lymphoid Enhancing Factor Transcriptional Activity and Collagen Type II Expression in Articular Chondrocytes through Formation of Gli3R·α-Catenin·β-Catenin Ternary Complex." Journal of Biological Chemistry 287, no. 15 (February 1, 2012): 11751–60. http://dx.doi.org/10.1074/jbc.m111.281014.
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Chondrocytes, a unique cell type in cartilage tissue, are responsible for the regulation of anabolic and catabolic homeostasis in cartilage-specific extracellular matrix synthesis. Activation of Wnt/β-catenin signaling induces dedifferentiation of articular chondrocytes, resulting in suppression of type II collagen expression. We have shown previously that α-catenin inhibits β-catenin-Tcf/Lef (T-cell factor/lymphoid-enhancing factor) transcriptional activity in articular chondrocytes with a concomitant recovery of type II collagen expression. In the current study, we elucidated the mechanism underlying this inhibition of β-catenin-Tcf/Lef transcriptional activity by α-catenin, showing that it requires direct interaction between α-catenin and β-catenin. We further showed that it involves recruitment of Gli3R, the short transcription-repressing form of the transcription factor Gli3, to β-catenin by α-catenin. The resulting inhibition of β-catenin transcriptional activity leads to increased expression of type II collagen. Gli3R and α-catenin actions are co-dependent: both are necessary for the observed inhibitory effects on β-catenin transcriptional activity. Reducing Gli3R expression levels through activation of Indian Hedgehog (Ihh) signaling also is sufficient to activate β-catenin transcriptional activity, suggesting that the ternary complex, Gli3R·α-catenin·β-catenin, mediates Ihh-dependent activation of Wnt/β-catenin signaling in articular chondrocytes. Collectively, this study shows that α-catenin functions as a nuclear factor that recruits the transcriptional repressor Gli3R to β-catenin to inhibit β-catenin transcriptional activity and dedifferentiation of articular chondrocytes. Finally, osteoarthritic cartilage showed elevated levels of β-catenin and decreased levels of α-catenin and Gli3R, suggesting that decreased levels of α-catenin and Gli3R levels contribute to increased β-catenin transcriptional activity during osteoarthritic cartilage destruction.
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Keating, David H. "Sinorhizobium meliloti SyrA Mediates the Transcriptional Regulation of Genes Involved in Lipopolysaccharide Sulfation and Exopolysaccharide Biosynthesis." Journal of Bacteriology 189, no. 6 (January 5, 2007): 2510–20. http://dx.doi.org/10.1128/jb.01803-06.
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ABSTRACT Sinorhizobium meliloti is a gram-negative soil bacterium found either in free-living form or as a nitrogen-fixing endosymbiont of leguminous plants such as Medicago sativa (alfalfa). S. meliloti synthesizes an unusual sulfate-modified form of lipopolysaccharide (LPS). A recent study reported the identification of a gene, lpsS, which encodes an LPS sulfotransferase activity in S. meliloti. Mutants bearing a disrupted version of lpsS exhibit an altered symbiosis, in that they elicit more nodules than wild type. However, under free-living conditions, the lpsS mutant displayed no change in LPS sulfation. These data suggest that the expression of lpsS is differentially regulated, such that it is transcriptionally repressed during free-living conditions but upregulated during symbiosis. Here, I show that the expression of lpsS is upregulated in strains that constitutively express the symbiotic regulator SyrA. SyrA is a small protein that lacks an apparent DNA binding domain and is predicted to be located in the cytoplasmic membrane yet is sufficient to upregulate lpsS transcription. Furthermore, SyrA can mediate the transcriptional upregulation of exo genes involved in the biosynthesis of the symbiotic exopolysaccharide succinoglycan. The SyrA-mediated transcriptional upregulation of lpsS and exo transcription is blocked in mutants harboring a mutation in chvI, which encodes the response regulator of a conserved two-component system. Thus, SyrA likely acts indirectly to promote transcriptional upregulation of lpsS and exo genes through a mechanism that requires the ExoS/ChvI two-component system.
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Chou, Yu-Chi, King-Song Jeng, Mong-Liang Chen, Hsiao-Hui Liu, Tzu-Ling Liu, Ya-Ling Chen, Yu-Chih Liu, Cheng-po Hu, and Chungming Chang. "Evaluation of Transcriptional Efficiency of Hepatitis B Virus Covalently Closed Circular DNA by Reverse Transcription-PCR Combined with the Restriction Enzyme Digestion Method." Journal of Virology 79, no. 3 (February 1, 2005): 1813–23. http://dx.doi.org/10.1128/jvi.79.3.1813-1823.2005.
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ABSTRACT Virus persistence in chronic hepatitis B patients is due to the sustaining level of covalently closed circular DNA (cccDNA) within the nuclei of infected hepatocytes. In this study, we used a modified 1.3-fold hepatitis B virus (HBV) genome, with a BclI genetic marker embedded in the redundancy region, to examine the transcriptional activity of cccDNA and the effect of the HBx protein on transcriptional regulation. After harvesting total RNA from transfected cells or stable lines, we specifically identified and monitored the transcripts from cccDNA by using reverse transcription-PCR (RT-PCR) combined with the restriction enzyme digestion method. In this approach, we have found that (i) RT-PCR combined with detection of the BclI marker is a highly specific method for distinguishing cccDNA-derived transcripts from the original integrated viral genome, (ii) the transcriptional ability of cccDNA was less efficient than that from the integrated viral genome, and (iii) the transcriptional activity of cccDNA was significantly regulated by the HBx protein, a potential transcription activator. In conclusion, we provided a tool with which to elucidate the transcriptional regulation of cccDNA and clarified the transcriptional regulation mechanism of HBx on cccDNA. The results obtained may be helpful in the development of a clinical intervention for patients with chronic HBV infections.
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Maeda, Yutaka, Vrushank Davé, and Jeffrey A. Whitsett. "Transcriptional Control of Lung Morphogenesis." Physiological Reviews 87, no. 1 (January 2007): 219–44. http://dx.doi.org/10.1152/physrev.00028.2006.
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The vertebrate lung consists of multiple cell types that are derived primarily from endodermal and mesodermal compartments of the early embryo. The process of pulmonary organogenesis requires the generation of precise signaling centers that are linked to transcriptional programs that, in turn, regulate cell numbers, differentiation, and behavior, as branching morphogenesis and alveolarization proceed. This review summarizes knowledge regarding the expression and proposed roles of transcription factors influencing lung formation and function with particular focus on knowledge derived from the study of the mouse. A group of transcription factors active in the endodermally derived cells of the developing lung tubules, including thyroid transcription factor-1 (TTF-1), β-catenin, Forkhead orthologs (FOX), GATA, SOX, and ETS family members are required for normal lung morphogenesis and function. In contrast, a group of distinct proteins, including FOXF1, POD1, GLI, and HOX family members, play important roles in the developing lung mesenchyme, from which pulmonary vessels and bronchial smooth muscle develop. Lung formation is dependent on reciprocal signaling among cells of both endodermal and mesenchymal compartments that instruct transcriptional processes mediating lung formation and adaptation to breathing after birth.
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Li, Juan, Baotong Zhang, Mingcheng Liu, Xing Fu, Xinpei Ci, Jun A, Changying Fu, et al. "KLF5 Is Crucial for Androgen-AR Signaling to Transactivate Genes and Promote Cell Proliferation in Prostate Cancer Cells." Cancers 12, no. 3 (March 21, 2020): 748. http://dx.doi.org/10.3390/cancers12030748.
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Androgen/androgen receptor (AR) signaling drives both the normal prostate development and prostatic carcinogenesis, and patients with advanced prostate cancer often develop resistance to androgen deprivation therapy. The transcription factor Krüppel-like factor 5 (KLF5) also regulates both normal and cancerous development of the prostate. In this study, we tested whether and how KLF5 plays a role in the function of AR signaling in prostate cancer cells. We found that KLF5 is upregulated by androgen depending on AR in LNCaP and C4-2B cells. Silencing KLF5, in turn, reduced AR transcriptional activity and inhibited androgen-induced cell proliferation and tumor growth in vitro and in vivo. Mechanistically, KLF5 occupied the promoter of AR, and silencing KLF5 repressed AR transcription. In addition, KLF5 and AR physically interacted with each other to regulate the expression of multiple genes (e.g., MYC, CCND1 and PSA) to promote cell proliferation. These findings indicate that, while transcriptionally upregulated by AR signaling, KLF5 also regulates the expression and transcriptional activity of AR in androgen-sensitive prostate cancer cells. The KLF5-AR interaction could provide a therapeutic opportunity for the treatment of prostate cancer.
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García-García, Laura, Enrique Fernández-Tabanera, Saint T. Cervera, Raquel M. Melero-Fernández de Mera, Santiago Josa, Laura González-González, Carlos Rodríguez-Martín, Thomas G. P. Grünewald, and Javier Alonso. "The Transcription Factor FEZF1, a Direct Target of EWSR1-FLI1 in Ewing Sarcoma Cells, Regulates the Expression of Neural-Specific Genes." Cancers 13, no. 22 (November 12, 2021): 5668. http://dx.doi.org/10.3390/cancers13225668.
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Ewing sarcoma is a rare pediatric tumor characterized by chromosomal translocations that give rise to aberrant chimeric transcription factors (e.g., EWSR1-FLI1). EWSR1-FLI1 promotes a specific cellular transcriptional program. Therefore, the study of EWSR1-FLI1 target genes is important to identify critical pathways involved in Ewing sarcoma tumorigenesis. In this work, we focused on the transcription factors regulated by EWSR1-FLI1 in Ewing sarcoma. Transcriptomic analysis of the Ewing sarcoma cell line A673 indicated that one of the genes more strongly upregulated by EWSR1-FLI1 was FEZF1 (FEZ family zinc finger protein 1), a transcriptional repressor involved in neural cell identity. The functional characterization of FEZF1 was performed in three Ewing sarcoma cell lines (A673, SK-N-MC, SK-ES-1) through an shRNA-directed silencing approach. FEZF1 knockdown inhibited clonogenicity and cell proliferation. Finally, the analysis of the FEZF1-dependent expression profile in A673 cells showed several neural genes regulated by FEZF1 and concomitantly regulated by EWSR1-FLI1. In summary, FEZF1 is transcriptionally regulated by EWSR1-FLI1 in Ewing sarcoma cells and is involved in the regulation of neural-specific genes, which could explain the neural-like phenotype observed in several Ewing sarcoma tumors and cell lines.
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Jackson, Kelly A., Ruth A. Valentine, Lisa J. Coneyworth, John C. Mathers, and Dianne Ford. "Mechanisms of mammalian zinc-regulated gene expression." Biochemical Society Transactions 36, no. 6 (November 19, 2008): 1262–66. http://dx.doi.org/10.1042/bst0361262.
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Mechanisms through which gene expression is regulated by zinc are central to cellular zinc homoeostasis. In this context, evidence for the involvement of zinc dyshomoeostasis in the aetiology of diseases, including Type 2 diabetes, Alzheimer's disease and cancer, highlights the importance of zinc-regulated gene expression. Mechanisms elucidated in bacteria and yeast provide examples of different possible modes of zinc-sensitive gene regulation, involving the zinc-regulated binding of transcriptional activators and repressors to gene promoter regions. A mammalian transcriptional regulatory mechanism that mediates zinc-induced transcriptional up-regulation, involving the transcription factor MTF1 (metal-response element-binding transcription factor 1), has been studied extensively. Gene responses in the opposite direction (reduced mRNA levels in response to increased zinc availability) have been observed in mammalian cells, but a specific transcriptional regulatory process responsible for such a response has yet to be identified. Examples of single zinc-sensitive transcription factors regulating gene expression in opposite directions are emerging. Although zinc-induced transcriptional repression by MTF1 is a possible explanation in some specific instances, such a mechanism cannot account for repression by zinc of all mammalian genes that show this mode of regulation, indicating the existence of as yet uncharacterized mechanisms of zinc-regulated transcription in mammalian cells. In addition, recent findings reveal a role for effects of zinc on mRNA stability in the regulation of specific zinc transporters. Our studies on the regulation of the human gene SLC30A5 (solute carrier 30A5), which codes for the zinc transporter ZnT5, have revealed that this gene provides a model system by which to study both zinc-induced transcriptional down-regulation and zinc-regulated mRNA stabilization.
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Wan, Yakun, Christina E. Arens, Steven Wang, Xiao Zuo, Ya Zhuo, Jie Xing, and Hongde Liu. "Role of the repressor Oaf3p in the recruitment of transcription factors and chromatin dynamics during the oleate response." Biochemical Journal 449, no. 2 (December 14, 2012): 507–17. http://dx.doi.org/10.1042/bj20121029.
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Cellular responses to environmental stimuli are mediated by the co-ordinated activity of multiple control mechanisms, which result in the dynamics of cell function. Communication between different levels of regulation is central for this adaptability. The present study focuses on the interplay between transcriptional regulators and chromatin modifiers to co-operatively regulate transcription in response to a fatty acid stimulus. The genes involved in the β-oxidation of fatty acids are highly induced in response to fatty acid exposure by four gene-specific transcriptional regulators, Oaf (oleate-activated transcription factor) 1p, Pip2p (peroxisome induction pathway 2), Oaf3p and Adr1p (alcohol dehydrogenase regulator 1). In the present study, we examine the interplay of these factors with Htz1p (histone variant H2A.Z) in regulating POT1 (peroxisomal oxoacyl thiolase 1) encoding peroxisomal thiolase and PIP2 encoding the autoregulatory oleate-specific transcriptional activator. Temporal resolution of ChIP (chromatin immunoprecipitation) data indicates that Htz1p is required for the timely removal of the transcriptional repressor Oaf3p during oleate induction. Adr1p plays an important role in the assembly of Htz1p-containing nucleosomes on the POT1 and PIP2 promoters. We also investigated the function of the uncharacterized transcriptional inhibitor Oaf3p. Deletion of OAF3 led to faster POT1 mRNA accumulation than in the wild-type. Most impressively, a highly protected nucleosome structure on the POT1 promoter during activation was observed in the OAF3 mutant cells in response to oleate induction.
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Colgin, Mark A., and Jennifer K. Nyborg. "The Human T-Cell Leukemia Virus Type 1 Oncoprotein Tax Inhibits the Transcriptional Activity of c-Myb through Competition for the CREB Binding Protein." Journal of Virology 72, no. 11 (November 1, 1998): 9396–99. http://dx.doi.org/10.1128/jvi.72.11.9396-9399.1998.
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ABSTRACT Tax, the transforming protein of human T-cell leukemia virus type 1 (HTLV-1), is required for strong activation of HTLV-1 transcription. This activation is mediated through interaction with the KIX domain of the cellular coactivator CREB binding protein (CBP). In this study we examined the possibility that the Tax-KIX interaction may mediate effects on cellular gene transcription in vivo, as a growing number of cellular transcription factors have been shown to utilize CBP as a coactivator. We tested the ability of Tax to deregulate the activity of the cellular transcription factor, c-Myb, since both Tax and c-Myb interact with the KIX domain of CBP. Our results show that in vivo, Tax antagonizes the transcriptional activity of c-Myb and, reciprocally, c-Myb antagonizes the transcriptional activity of Tax. Furthermore, c-Myb competes for KIX binding to Tax in vitro, indicating that these two transcription factors bind CBP in a mutually exclusive manner. This novel mechanism of transcriptional interference by Tax may promote globally deregulated cellular gene expression in the HTLV-1-infected cell, possibly leading to leukemogenesis.
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Tong, Yunguang, and Tamar Eigler. "Transcriptional targets for pituitary tumor-transforming gene-1." Journal of Molecular Endocrinology 43, no. 5 (May 11, 2009): 179–85. http://dx.doi.org/10.1677/jme-08-0176.
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Pituitary tumor-transforming gene-1 (PTTG1) is a transforming gene first discovered in rat pituitary tumor cells. It possesses transcriptional activity and also has securin functions. Chromatin immunoprecipitation-on-chip study reveals that PTTG1 is a global transcription factor, which exerts its transcriptional activity either by directly binding to DNA or by interacting with proteins including PTTG1 binding factor, p53, Sp1, and upstream stimulatory factor 1. PTTG1 has several validated transcriptional targets that are involved in different cellular processes. PTTG1 activates c-Myc in NIH 3T3 cells, suggesting a role in cell transformation. PTTG1 induces fibroblast growth factor 2 expression and promotes tumor angiogenesis.It binds to and inhibits p53 transcriptional activity. PTTG1 activates cyclin D3 and represses p21 expression, indicating a role in cell cycle regulation and cell senescence. Here, we review PTTG1 transcriptional targets and their functions.
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Taniuchi, Fumiko, Koji Higai, Tomomi Tanaka, Yutaro Azuma, and Kojiro Matsumoto. "Transcriptional Regulation ofFucosyltransferase 1Gene Expression in Colon Cancer Cells." Scientific World Journal 2013 (2013): 1–9. http://dx.doi.org/10.1155/2013/105464.
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Theα1,2-fucosyltransferase I (FUT1) enzyme is important for the biosynthesis of H antigens, Lewis B, and Lewis Y. In this study, we clarified the transcriptional regulation of FUT1 in the DLD-1 colon cancer cell line, which has high expression of Lewis B and Lewis Y antigens, expresses theFUT1gene, and showsα1,2-fucosyltransferase (FUT) activity. 5′-rapid amplification of cDNA ends revealed a FUT1 transcriptional start site −10 nucleotides upstream of the site registered at NM_000148 in the DataBase of Human Transcription Start Sites (DBTSS). Using the dual luciferase assay,FUT1gene expression was shown to be regulated at the region −91 to −81 nt to the transcriptional start site, which contains the Elk-1 binding site. Site-directed mutagenesis of this region revealed the Elk-1 binding site to be essential for FUT1 transcription. Furthermore, transfection of the dominant negative Elk-1 gene, and the chromatin immunoprecipitation (CHIp) assay, supported Elk-1-dependent transcriptional regulation ofFUT1gene expression in DLD-1 cells. These results suggest that a defined region in the 5′-flanking region of FUT1 is critical for FUT1 transcription and that constitutive gene expression ofFUT1is regulated by Elk-1 in DLD-1 cells.
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McCall, G. E., D. L. Allen, F. Haddad, and K. M. Baldwin. "Transcriptional regulation of IGF-I expression in skeletal muscle." American Journal of Physiology-Cell Physiology 285, no. 4 (October 2003): C831—C839. http://dx.doi.org/10.1152/ajpcell.00047.2003.
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The present study investigated the role of transcription in the regulation of insulin-like growth factor (IGF)-I expression in skeletal muscle. RT-PCR was used to determine endogenous expression of IGF-I pre-mRNA and mRNA in control (Con) and functionally overloaded (FO) rat plantaris. The transcriptional activities of five different-length IGF-I promoter fragments controlling transcription of a firefly luciferase (FLuc) reporter gene were tested in vitro by transfection of myoblasts or in vivo during FO by direct gene transfer into the plantaris. Increased endogenous IGF-I gene transcription during 7 days of plantaris FO was evidenced by an ∼140-160% increase ( P < 0.0001) in IGF-I pre-mRNA (a transcriptional marker). IGF-I mRNA expression also increased by ∼90% ( P < 0.0001), and it was correlated ( R = 0.93; P < 0.0001) with the pre-mRNA increases. The three longest IGF-I exon 1 promoters induced reporter gene expression in proliferating C2C12 and L6E9 myoblasts. In differentiated L6E9 myotubes, promoter activity increased approximately two- to threefold over myoblasts. Overexpression of calcineurin and MyoD increased the activity of the -852/+192 promoter in C2C12 myotubes by ∼5- and ∼18-fold, respectively. However, FO did not induce these exogenous promoter fragments. Nevertheless, the present findings are consistent with the hypothesis that the IGF-I gene is transcriptionally regulated during muscle hypertrophy in vivo as evidenced by the induction of the endogenous IGF-I pre-mRNA during plantaris FO. The exon 1 promoter region of the IGF-I gene is sufficient to direct inducible expression in vitro; however, an in vivo response to FO may require elements outside the -852/+346 region of the exon 1 IGF-I promoter or features inherent to the endogenous IGF-I gene.
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Okitsu, Cindy Yen, and Chih-Lin Hsieh. "DNA Methylation Dictates Histone H3K4 Methylation." Molecular and Cellular Biology 27, no. 7 (January 22, 2007): 2746–57. http://dx.doi.org/10.1128/mcb.02291-06.
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ABSTRACT Histone lysine methylation and DNA methylation contribute to transcriptional regulation. We have previously shown that acetylated histones are associated with unmethylated DNA and are nearly absent from the methylated DNA regions by using patch-methylated stable episomes in human cells. The present study further demonstrates that DNA methylation immediately downstream from the transcription start site has a dramatic impact on transcription and that DNA methylation has a larger effect on transcription elongation than on initiation. We also show that dimethylated histone H3 at lysine 4 (H3K4me2) is depleted from regions with DNA methylation and that this effect is not linked to the transcriptional activity in the region. This effect is a local one and does not extend even 200 bp from the methylated DNA regions. Although depleted primarily from the methylated DNA regions, the presence of trimethylated histone H3 at lysine 4 (H3K4me3) may be affected by transcriptional activity as well. The data here suggest that DNA methylation at the junction of transcription initiation and elongation is most critical in transcription suppression and that this effect is mechanistically mediated through chromatin structure. The data also strongly support the model in which DNA methylation and not transcriptional activity dictates a closed chromatin structure, which excludes H3K4me2 and H3K4me3 in the region, as one of the pathways that safeguards the silent state of genes.
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Desai, Ravi V., Xinyue Chen, Benjamin Martin, Sonali Chaturvedi, Dong Woo Hwang, Weihan Li, Chen Yu, et al. "A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions." Science 373, no. 6557 (July 22, 2021): eabc6506. http://dx.doi.org/10.1126/science.abc6506.
Full textAbstract:
Stochastic fluctuations in gene expression (“noise”) are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean expression levels. This amplified expression noise originates from shorter-duration, higher-intensity transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels. This mechanism, which we refer to as “discordant transcription through repair” (“DiThR,” which is pronounced “dither”), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.
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Bjørkhaug, Lise, André Bratland, Pål Rasmus Njølstad, and Anders Molven. "Functional Dissection of the HNF-1alpha Transcription Factor: A Study on Nuclear Localization and Transcriptional Activation." DNA and Cell Biology 24, no. 11 (November 2005): 661–69. http://dx.doi.org/10.1089/dna.2005.24.661.
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Han, Qiuju, Jun Lu, Jizhou Duan, Dongmei Su, Xiaozhe Hou, Fen Li, Xiuli Wang, and Baiqu Huang. "Gcn5- and Elp3-induced histone H3 acetylation regulates hsp70 gene transcription in yeast." Biochemical Journal 409, no. 3 (January 15, 2008): 779–88. http://dx.doi.org/10.1042/bj20070578.
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The purpose of this study was to elucidate the mechanisms by which histone acetylation participates in transcriptional regulation of hsp70 (heat-shock protein 70) genes SSA3 and SSA4 in yeast. Our results indicated that histone acetylation was required for the transcriptional activation of SSA3 and SSA4. The HATs (histone acetyltransferases) Gcn5 (general control non-derepressible 5) and Elp3 (elongation protein 3) modulated hsp70 gene transcription by affecting the acetylation status of histone H3. Although the two HATs possessed overlapping function regarding the acetylation of histone H3, they affected hsp70 gene transcription in different ways. The recruitment of Gcn5 was Swi/Snf-dependent and was required for HSF (heat-shock factor) binding and affected RNAPII (RNA polymerase II) recruitment, whereas Elp3 exerted its roles mainly through affecting RNAPII elongation. These results provide insights into the effects of Gcn5 and Elp3 in hsp70 gene transcription and underscore the importance of histone acetylation for transcriptional initiation and elongation in hsp genes.
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Johnson, Lisa A., Ying Zhao, Krista Golden, and Scott Barolo. "Reverse-Engineering a Transcriptional Enhancer: A Case Study inDrosophila." Tissue Engineering Part A 14, no. 9 (September 2008): 1549–59. http://dx.doi.org/10.1089/ten.tea.2008.0074.
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