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Activation of silent gene cluster

Yutong Shi, Chengqian Pan, Bibi Nazia Auckloo, Xuegang Chen, Chen-Tung Arthur Chen, Kuiwu Wang, Xiaodan Wu, Ying Ye, Bin Wu
Marine hydrothermal microorganisms respond rapidly to the changes in the concentrations and availability of metals within hydrothermal vent microbial habitats which are strongly influenced by elevated levels of heavy metals. Most hydrothermal vent actinomycetes possess a remarkable capability for the synthesis of a broad variety of biologically active secondary metabolites. Major challenges in the screening of these microorganisms are to activate the expression of cryptic biosynthetic gene clusters and the development of technologies for efficient dereplication of known compounds...
October 11, 2016: Applied Microbiology and Biotechnology
Pouria HosseinNia, Mehdi Hajian, Mojtaba Tahmoorespur, Sayyed Morteza Hosseini, Somayyeh Ostadhosseini, Mohammad Reza Nasiri, Mohammad Hossein Nasr-Esfahani
BACKGROUND: Little is understood about the regulation of gene expression during early goat embryo development. This study investigated the expression profile of 19 genes, known to be critical for early embryo development in mouse and human, at five different stages of goat in vitro embryo development (oocyte, 8-16 cell, morula, day-7 blastocyst, and day 14 blastocyst). MATERIALS AND METHODS: In this experimental study, stage-specific profiling using real time-quantitative polymerase chain reaction (RT-qPCR) revealed robust and dynamic patterns of stage-specific gene activity that fall into four major clusters depending on their respective mRNA profiles...
October 2016: International Journal of Fertility & Sterility
Zhibo Ma, Mo Li, Sharmila Roy, Kevin J Liu, Matthew L Romine, Derrick C Lane, Sapna K Patel, Haini N Cai
The three-dimensional (3D) organization of the eukaryotic genome is critical for its proper function. Evidence suggests that extensive chromatin loops form the building blocks of the genomic architecture, separating genes and gene clusters into distinct functional domains. These loops are anchored in part by a special type of DNA elements called chromatin boundary elements (CBEs). CBEs were originally found to insulate neighboring genes by blocking influences of transcriptional enhancers or the spread of silent chromatin...
August 26, 2016: World Journal of Biological Chemistry
Olga N Sekurova, Ignacio Pérez-Victoria, Jesús Martín, Kristin F Degnes, Håvard Sletta, Fernando Reyes, Sergey B Zotchev
Activation of silent biosynthetic gene clusters in Streptomyces bacteria via overexpression of cluster-specific regulatory genes is a promising strategy for the discovery of novel bioactive secondary metabolites. This approach was used in an attempt to activate a cryptic gene cluster in a marine sponge-derived Streptomyces albus PVA94-07 presumably governing the biosynthesis of peptide-based secondary metabolites. While no new peptide-based metabolites were detected in the recombinant strain, it was shown to produce at least four new analogues of deferoxamine with additional acyl and sugar moieties, for which chemical structures were fully elucidated...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Anyarat Thanapipatsiri, Juan Pablo Gomez-Escribano, Lijiang Song, Maureen Bibb, Mahmoud Al-Bassam, Govind Chandra, Arinthip Thamchaipenet, Greg Challis, Mervyn Bibb
Comparative transcriptional profiling of a ΔbldM mutant of Streptomyces venezuelae with its unmodified progenitor revealed that the expression of a cryptic biosynthetic gene cluster containing both Type I and Type III polyketide synthase genes is activated in the mutant. The 29.5 kb gene cluster, which was predicted to encode an unusual biaryl metabolite, venemycin, and potentially halogenated derivatives, contains 17 genes including one, vemR, encoding a transcriptional activator of the large ATP-binding LuxR-like (LAL) family...
September 8, 2016: Chembiochem: a European Journal of Chemical Biology
Bethany K Okada, Mohammad R Seyedsayamdost
Natural products have traditionally served as a dominant source of therapeutic agents. They are produced by dedicated biosynthetic gene clusters that assemble complex, bioactive molecules from simple precursors. Recent genome sequencing efforts coupled with advances in bioinformatics indicate that the majority of biosynthetic gene clusters are not expressed under normal laboratory conditions. Termed 'silent' or 'cryptic', these gene clusters represent a treasure trove for discovery of novel small molecules, their regulatory circuits and their biosynthetic pathways...
August 29, 2016: FEMS Microbiology Reviews
Agnieszka Gacek-Matthews, Harald Berger, Takahiko Sasaki, Kathrin Wittstein, Clemens Gruber, Zachary A Lewis, Joseph Strauss
Histone posttranslational modifications (HPTMs) are involved in chromatin-based regulation of fungal secondary metabolite biosynthesis (SMB) in which the corresponding genes-usually physically linked in co-regulated clusters-are silenced under optimal physiological conditions (nutrient-rich) but are activated when nutrients are limiting. The exact molecular mechanisms by which HPTMs influence silencing and activation, however, are still to be better understood. Here we show by a combined approach of quantitative mass spectrometry (LC-MS/MS), genome-wide chromatin immunoprecipitation (ChIP-seq) and transcriptional network analysis (RNA-seq) that the core regions of silent A...
August 2016: PLoS Genetics
Diogo Pimentel, Jeffrey M Donlea, Clifford B Talbot, Seoho M Song, Alexander J F Thurston, Gero Miesenböck
Sleep disconnects animals from the external world, at considerable risks and costs that must be offset by a vital benefit. Insight into this mysterious benefit will come from understanding sleep homeostasis: to monitor sleep need, an internal bookkeeper must track physiological changes that are linked to the core function of sleep. In Drosophila, a crucial component of the machinery for sleep homeostasis is a cluster of neurons innervating the dorsal fan-shaped body (dFB) of the central complex. Artificial activation of these cells induces sleep, whereas reductions in excitability cause insomnia...
August 18, 2016: Nature
Maksym Myronovskyi, Andriy Luzhetskyy
Covers the period up to 2016Bacterial-based natural products have long represented a promising resource for the development of commercially relevant therapeutics, and more than two thirds of these products have been developed from members of the genus Streptomyces. The extensive sequencing of bacterial genomes suggests that the majority of gene clusters encoding natural products are silent and not expressed under standard laboratory conditions. However, these clusters can be activated through systematic exchanges between native transcriptionally silent promoters and transcriptionally active promoters...
August 27, 2016: Natural Product Reports
Luca Giorgetti, Bryan R Lajoie, Ava C Carter, Mikael Attia, Ye Zhan, Jin Xu, Chong Jian Chen, Noam Kaplan, Howard Y Chang, Edith Heard, Job Dekker
X-chromosome inactivation (XCI) involves major reorganization of the X chromosome as it becomes silent and heterochromatic. During female mammalian development, XCI is triggered by upregulation of the non-coding Xist RNA from one of the two X chromosomes. Xist coats the chromosome in cis and induces silencing of almost all genes via its A-repeat region, although some genes (constitutive escapees) avoid silencing in most cell types, and others (facultative escapees) escape XCI only in specific contexts. A role for Xist in organizing the inactive X (Xi) chromosome has been proposed...
July 28, 2016: Nature
Mia Urem, Magdalena Swiatek-Polatynska, Sébastien Rigali, Gilles P van Wezel
Actinobacteria are producers of a plethora of natural products of agricultural, biotechnological and clinical importance. In an era where mankind has to deal with rapidly spreading antimicrobial resistance, streptomycetes are of particular importance as producers of half of all antibiotics used in the clinic. Genome sequencing efforts revealed that their capacity as antibiotic producers has been underestimated, in particular as many biosynthetic pathways are silent under standard laboratory conditions. Here we review the global regulatory networks that control antibiotic production in streptomycetes, with emphasis on carbon- and aminosugar-related nutrient sensory pathways...
July 18, 2016: Molecular Microbiology
Bethany K Okada, Yihan Wu, Dainan Mao, Leah B Bushin, Mohammad R Seyedsayamdost
While bacterial genomes typically contain numerous secondary metabolite biosynthetic gene clusters, only a small fraction of these are expressed at any given time. The remaining majority is inactive or silent, and methods that awaken them would greatly expand our repertoire of bioactive molecules. We recently devised a new approach for identifying inducers of silent gene clusters and proposed that the clinical antibiotic trimethoprim acted as a global activator of secondary metabolism in Burkholderia thailandensis...
August 19, 2016: ACS Chemical Biology
Meric A Altinoz, Emin M Ozcan, Bahri Ince, Sinan Guloksuz
Basic science investigations and clinical observations in recent years indicate that hemoglobins (Hbs) may have important roles in the pathogenesis of multiple sclerosis (MS). These findings can be summarized as follows: 1- Erythrocyte fragility is higher in MS patients, the released free Hb damages blood-brain barrier, myelin basic protein and also triggers iron overload and inflammation. 2- Free Hb may further activate the inflammatory responses through Toll-like receptor 4 (TLR4), present on microglia and other innate immunocytes...
October 2016: Metabolic Brain Disease
Sonia Giubergia, Christopher Phippen, Charlotte H Gotfredsen, Kristian Fog Nielsen, Lone Gram
UNLABELLED: Many factors, such as the substrate and the growth phase, influence biosynthesis of secondary metabolites in microorganisms. Therefore, it is crucial to consider these factors when establishing a bioprospecting strategy. Mimicking the conditions of the natural environment has been suggested as a means of inducing or influencing microbial secondary metabolite production. The purpose of the present study was to determine how the bioactivity of Vibrionaceae was influenced by carbon sources typical of their natural environment...
July 1, 2016: Applied and Environmental Microbiology
Weishan Wang, Tongjian Yang, Yihong Li, Shanshan Li, Shouliang Yin, Kathryn Styles, Christophe Corre, Keqian Yang
Precise control of gene expression using exogenous factors is of great significance. To develop ideal inducible expression systems for streptomycetes, new genetic parts, oxytetracycline responsive repressor OtrR, operator otrO, and promoter otrBp from Streptomyces rimosus, were selected de novo and characterized in vivo and in vitro. OtrR showed strong affinity to otrO (KD = 1.7 × 10(-10) M) and oxytetracycline induced dissociation of the OtrR/DNA complex in a concentration-dependent manner. On the basis of these genetic parts, a synthetic inducible expression system Potr* was optimized...
July 15, 2016: ACS Synthetic Biology
Alexandra A Soukup, Nancy P Keller, Philipp Wiemann
Filamentous fungi are historically known as rich sources for production of biologically active natural products, so-called secondary metabolites. One particularly pharmaceutically relevant chemical group of secondary metabolites is the nonribosomal peptides synthesized by nonribosomal peptide synthetases (NRPSs). As most of the fungal NRPS gene clusters leading to production of the desired molecules are not expressed under laboratory conditions, efforts to overcome this impediment are crucial to unlock the full chemical potential of each fungal species...
2016: Methods in Molecular Biology
Paulina Bekiesch, Mirita Franz-Wachtel, Andreas Kulik, Melanie Brocker, Karl Forchhammer, Bertolt Gust, Alexander Kristian Apel
Understanding the regulation of a heterologously expressed gene cluster in a host organism is crucial for activation of silent gene clusters or overproduction of the corresponding natural product. In this study, Streptomyces coelicolor M512(nov-BG1) containing the novobiocin biosynthetic gene cluster from Streptomyces niveus NCIMB 11891 was chosen as a model. An improved DNA affinity capturing assay (DACA), combined with semi-quantitative mass spectrometry, was used to identify proteins binding to the promoter regions of the novobiocin gene cluster...
May 2016: Applied Microbiology and Biotechnology
Joseph Scott Zarins-Tutt, Tania Triscari Barberi, Hong Gao, Andrew Mearns-Spragg, Lixin Zhang, David J Newman, Rebecca Jane Miriam Goss
Covering: up to 2015. Over the centuries, microbial secondary metabolites have played a central role in the treatment of human diseases and have revolutionised the pharmaceutical industry. With the increasing number of sequenced microbial genomes revealing a plethora of novel biosynthetic genes, natural product drug discovery is entering an exciting second golden age. Here, we provide a concise overview as an introductory guide to the main methods employed to unlock or up-regulate these so called 'cryptic', 'silent' and 'orphan' gene clusters, and increase the production of the encoded natural product...
January 2016: Natural Product Reports
Paul Sweeney, Cormac D Murphy, Patrick Caffrey
The genome of the amphotericin producer Streptomyces nodosus was sequenced. A single scaffold of 7,714,110 bp was obtained. Biosynthetic genes were identified for several natural products including polyketides, peptides, siderophores and terpenes. The majority of these clusters specified known compounds. Most were silent or expressed at low levels and unlikely to compete with amphotericin production. Biosynthesis of a skyllamycin analogue was activated by introducing expression plasmids containing either a gene for a LuxR transcriptional regulator or genes for synthesis of the acyl moiety of the lipopeptide...
October 26, 2015: Applied Microbiology and Biotechnology
Tiago Beites, Marta V Mendes
The increased number of bacterial genome sequencing projects has generated over the last years a large reservoir of genomic information. In silico analysis of this genomic data has renewed the interest in bacterial bioprospecting for bioactive compounds by unveiling novel biosynthetic gene clusters of unknown or uncharacterized metabolites. However, only a small fraction of those metabolites is produced under laboratory-controlled conditions; the remaining clusters represent a pool of novel metabolites that are waiting to be "awaken"...
2015: Frontiers in Microbiology
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