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Activation of silent gene cluster

Layal Abo Khayal, Johannes Grünhagen, Ivo Provazník, Stefan Mundlos, Uwe Kornak, Peter N Robinson, Claus-Eric Ott
Osteoblastic differentiation is a multistep process characterized by osteogenic induction of mesenchymal stem cells, which then differentiate into proliferative pre-osteoblasts that produce copious amounts of extracellular matrix, followed by stiffening of the extracellular matrix, and matrix mineralization by hydroxylapatite deposition. Although these processes have been well characterized biologically, a detailed transcriptional analysis of murine primary calvaria osteoblast differentiation based on RNA sequencing (RNA-seq) analyses has not previously been reported...
April 10, 2018: Bone
Kenji Arakawa
Streptomyces is well characterized by an ability to produce a wide variety of secondary metabolites including antibiotics, whose expression is strictly controlled by small diffusible signaling molecules at nano-molar concentrations. The signaling molecules identified to date are classified into three skeletons; γ-butyrolactones, furans, and γ-butenolides. Accumulated data suggest the structural diversity of the signaling molecules in Streptomyces species and their potential in activating cryptic secondary metabolite biosynthetic pathways...
February 23, 2018: Antonie Van Leeuwenhoek
Francesco Alessandro Massucci, Francesc Sagués, M Ángeles Serrano
The most frequent form of pairwise synthetic lethality (SL) in metabolic networks is known as plasticity synthetic lethality. It occurs when the simultaneous inhibition of paired functional and silent metabolic reactions or genes is lethal, while the default of the functional partner is backed up by the activation of the silent one. Using computational techniques on bacterial genome-scale metabolic reconstructions, we found that the failure of the functional partner triggers a critical reorganization of fluxes to ensure viability in the mutant which not only affects the SL pair but a significant fraction of other interconnected reactions, forming what we call a SL cluster...
January 30, 2018: PLoS Computational Biology
Slavica Janevska, Bettina Tudzynski
The fungus Fusarium fujikuroi causes bakanae disease of rice due to its ability to produce the plant hormones, the gibberellins. The fungus is also known for producing harmful mycotoxins (e.g., fusaric acid and fusarins) and pigments (e.g., bikaverin and fusarubins). However, for a long time, most of these well-known products could not be linked to biosynthetic gene clusters. Recent genome sequencing has revealed altogether 47 putative gene clusters. Most of them were orphan clusters for which the encoded natural product(s) were unknown...
January 2018: Applied Microbiology and Biotechnology
Jenny Welander, Małgorzata Łysiak, Michael Brauckhoff, Laurent Brunaud, Peter Söderkvist, Oliver Gimm
INTRODUCTION: Pheochromocytomas are neuroendocrine tumors of the adrenal glands. Up to 40% of the cases are caused by germline mutations in one of at least 15 susceptibility genes, making them the human neoplasms with the highest degree of heritability. Recurrent somatic alterations are found in about 50% of the more common sporadic tumors with NF1 being the most common mutated gene (20-25%). In many sporadic tumors, however, a genetic explanation is still lacking. MATERIALS AND METHODS: We investigated the genomic landscape of sporadic pheochromocytomas with whole-exome sequencing of 16 paired tumor and normal DNA samples and extended confirmation analysis in 2 additional cohorts comprising a total of 80 sporadic pheochromocytomas...
February 2018: World Journal of Surgery
Ramsay S T Kamdem, Hao Wang, Pascal Wafo, Weaam Ebrahim, Ferhat Can Özkaya, Gamall Makhloufi, Christoph Janiak, Parichat Sureechatchaiyan, Matthias U Kassack, Wenhan Lin, Zhen Liu, Peter Proksch
A new alkaloid, 1,2-dihydrophenopyrrozin (1), along with five known compounds (2-6) was isolated from an axenic culture of the endophytic fungus, Bionectria sp., obtained from seeds of the tropical plant Raphia taedigera. Co-cultivation of this fungus either with Bacillus subtilis or with Streptomyces lividans resulted in the production of two new o-aminobenzoic acid derivatives, bionectriamines A and B (7 and 8) as well as of two additional known compounds (9 and 10). None of the latter compounds (7-10) were detected in axenic cultures of the fungus or of the bacteria indicating activation of silent biogenetic gene clusters through co-cultivation with bacteria...
January 2018: Fitoterapia
Ruidong Chen, Qingbo Zhang, Bin Tan, Liujuan Zheng, Huixian Li, Yiguang Zhu, Changsheng Zhang
A 92 kb silent hybrid polyketide and nonribosomal peptide gene cluster in marine-derived Streptomyces pactum SCSIO 02999 was activated by genetically manipulating the regulatory genes, including the knockout of two negative regulators (totR5 and totR3) and overexpression of a positive regulator totR1, to direct the production of the known totopotensamides (TPMs) A (1) and B (3) and a novel sulfonate-containing analogue TPM C (2). Inactivation of totG led to accumulation of TPM B (3) lacking the glycosyl moiety, which indicated TotG as a dedicated glycosyltransferase in the biosynthesis of 1 and 2...
October 11, 2017: Organic Letters
Caroline Kreuzinger, Angelika Geroldinger, Dominiek Smeets, Elena Ioana Braicu, Jalid Sehouli, Julia Koller, Andrea Wolf, Silvia Darb-Esfahani, Korinna Joehrens, Ignace Vergote, Adriaan Vanderstichele, Bram Boeckx, Diether Lambrechts, Hani Gabra, G Bea A Wisman, Fabian Trillsch, Georg Heinze, Reinhard Horvat, Stephan Polterauer, Els Berns, Charles Theillet, Dan Cacsire Castillo-Tong
Purpose: Most high-grade serous ovarian cancer (HGSOC) patients develop recurrent disease after first-line treatment, frequently with fatal outcome. This work aims at studying the molecular biology of both primary and recurrent HGSOC. Experimental Design: Gene expression profiles of matched primary and recurrent fresh-frozen tumor tissues from 66 HGSOC patients were obtained by RNA sequencing. Clustering analyses and pairwise comparison of the profiles between matched samples and subsequent functional alignment were used for the identification of molecular characteristics of HGSOC...
December 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Ana Solopova, Jan Kok, Oscar P Kuipers
Lactococcus lactis subsp. cremoris strains typically carry many dairy niche-specific adaptations. During adaptation to the milk environment these former plant strains have acquired various pseudogenes and insertion sequence elements indicative of ongoing genome decay and frequent transposition events in their genomes. Here we describe the reactivation of a silenced plant sugar utilization cluster in an L. lactis MG1363 derivative lacking the two main cellobiose transporters, PtcBA-CelB and PtcBAC, upon applying selection pressure to utilize cellobiose...
December 1, 2017: Applied and Environmental Microbiology
Arthur Guljamow, Marco Kreische, Keishi Ishida, Anton Liaimer, Bjørn Altermark, Lars Bähr, Christian Hertweck, Rudolf Ehwald, Elke Dittmann
Terrestrial symbiotic cyanobacteria of the genus Nostoc exhibit a large potential for the production of bioactive natural products of the nonribosomal peptide, polyketide and ribosomal peptide classes, yet most of the biosynthetic gene clusters are silent under conventional cultivation conditions. In the present study, we have utilized a high-density cultivation approach recently developed for phototrophic bacteria to rapidly generate biomass of the filamentous bacteria up to a density of 400 g wet weight/L...
September 22, 2017: Applied and Environmental Microbiology
Shanren Li, Xiuli Wu, Limei Zhang, Yuemao Shen, Liangcheng Du
Lysobacter are considered "peptide specialists". However, many of the nonribosomal peptide synthetase genes are silent. Three new compounds were identified from L. enzymogenes upon activating the six-module-containing led cluster by the strong promoter PHSAF. Although ledD was the first gene under PHSAF control, the second gene ledE was expressed the highest. Targeted gene inactivation showed that the two-module LedE and the one-module LedF were selectively used in pyrrolopyrazine biosynthesis, revealing a module/domain portable mechanism...
October 6, 2017: Organic Letters
(no author information available yet)
This month: Lysosomal iron linked to cell death in cancer stem cells, non-enzymatic catalyst SynCAc for histone acylation, cytotoxins ivermectin and etoposide bring new anti-fungals out of the crypt, and 2'-deoxy-ADPR as second messenger activating TRPM2.
August 17, 2017: Cell Chemical Biology
Eva-Maria Niehaus, Julia Schumacher, Immo Burkhardt, Patrick Rabe, Eduard Spitzer, Martin Münsterkötter, Ulrich Güldener, Christian M K Sieber, Jeroen S Dickschat, Bettina Tudzynski
GATA-type transcription factors (TFs) such as the nitrogen regulators AreA and AreB, or the light-responsive TFs WC-1 and WC-2, play global roles in fungal growth and development. The conserved GATA TF NsdD is known as an activator of sexual development and key repressor of conidiation in Aspergillus nidulans, and as light-regulated repressor of macroconidia formation in Botrytis cinerea. In the present study, we functionally characterized the NsdD ortholog in Fusarium fujikuroi, named Csm1. Deletion of this gene resulted in elevated microconidia formation in the wild-type (WT) and restoration of conidiation in the non-sporulating velvet mutant Δvel1 demonstrating that Csm1 also plays a role as repressor of conidiation in F...
2017: Frontiers in Microbiology
Fei Xu, Behnam Nazari, Kyuho Moon, Leah B Bushin, Mohammad R Seyedsayamdost
An important unresolved issue in microbial secondary metabolite production is the abundance of biosynthetic gene clusters that are not expressed under typical laboratory growth conditions. These so-called silent or cryptic gene clusters are sources of new natural products, but how they are silenced, and how they may be rationally activated are areas of ongoing investigation. We recently devised a chemogenetic high-throughput screening approach ("HiTES") to discover small molecule elicitors of silent biosynthetic gene clusters...
July 12, 2017: Journal of the American Chemical Society
Navid Adnani, Scott R Rajski, Tim S Bugni
Covering: 2010 up to 2017Life on Earth is characterized by a remarkable abundance of symbiotic and highly refined relationships among life forms. Defined as any kind of close, long-term association between two organisms, symbioses can be mutualistic, commensalistic or parasitic. Historically speaking, selective pressures have shaped symbioses in which one organism (typically a bacterium or fungus) generates bioactive small molecules that impact the host (and possibly other symbionts); the symbiosis is driven fundamentally by the genetic machineries available to the small molecule producer...
July 6, 2017: Natural Product Reports
Christopher T Walsh
Antibiotics are a therapeutic class that, once deployed, select for resistant bacterial pathogens and so shorten their useful life cycles. As a consequence new versions of antibiotics are constantly needed. Among the antibiotic natural products, morphed peptide scaffolds, converting conformationally mobile, short-lived linear peptides into compact, rigidified small molecule frameworks, act on a wide range of bacterial targets. Advances in bacterial genome mining, biosynthetic gene cluster prediction and expression, and mass spectroscopic structure analysis suggests many more peptides, modified both in side chains and peptide backbones, await discovery...
July 1, 2017: Natural Product Reports
Subhasish Saha, Wenjun Zhang, Guangtao Zhang, Yiguang Zhu, Yuchan Chen, Wei Liu, Chengshan Yuan, Qingbo Zhang, Haibo Zhang, Liping Zhang, Weimin Zhang, Changsheng Zhang
Polycyclic tetramate macrolactams (PTMs) are a growing class of natural products and are derived from a hybrid polyketide synthase (PKS)/non-ribosomal peptide synthetase (NRPS) pathway. PTM biosynthetic gene clusters are conserved and widely distributed in bacteria, however, most of them remain silent. Herein we report the activation of a PTM gene cluster in marine-derived Streptomyces pactum SCSIO 02999 by promoter engineering and heterologous expression, leading to the discovery of six new PTMs, pactamides A-F (11-16), with potent cytotoxic activity upon several human cancer cell lines...
February 1, 2017: Chemical Science
Hiroyasu Onaka
Streptomyces have the potential to produce more than 30 secondary metabolites; however, the expression of most metabolite biosynthetic gene clusters is cryptic or silent. Indeed, the expression of these genes is conditional and dependent on culture conditions. To activate such gene clusters, many methods have been developed. In this review, I describe two activation approaches developed in my laboratory: use of the activation mediator goadsporin and combined-culture. Goadsporin is a chemical substance isolated from Streptomyces sp...
July 2017: Journal of Antibiotics
Mingzi M Zhang, Fong Tian Wong, Yajie Wang, Shangwen Luo, Yee Hwee Lim, Elena Heng, Wan Lin Yeo, Ryan E Cobb, Behnam Enghiad, Ee Lui Ang, Huimin Zhao
Here we report an efficient CRISPR-Cas9 knock-in strategy to activate silent biosynthetic gene clusters (BGCs) in streptomycetes. We applied this one-step strategy to activate multiple BGCs of different classes in five Streptomyces species and triggered the production of unique metabolites, including a novel pentangular type II polyketide in Streptomyces viridochromogenes. This potentially scalable strategy complements existing activation approaches and facilitates discovery efforts to uncover new compounds with interesting bioactivities...
April 10, 2017: Nature Chemical Biology
Slavica Janevska, Birgit Arndt, Leonie Baumann, Lisa Helene Apken, Lucas Maciel Mauriz Marques, Hans-Ulrich Humpf, Bettina Tudzynski
The PKS-NRPS-derived tetramic acid equisetin and its N-desmethyl derivative trichosetin exhibit remarkable biological activities against a variety of organisms, including plants and bacteria, e.g., Staphylococcus aureus. The equisetin biosynthetic gene cluster was first described in Fusarium heterosporum, a species distantly related to the notorious rice pathogen Fusarium fujikuroi. Here we present the activation and characterization of a homologous, but silent, gene cluster in F. fujikuroi. Bioinformatic analysis revealed that this cluster does not contain the equisetin N-methyltransferase gene eqxD and consequently, trichosetin was isolated as final product...
April 5, 2017: Toxins
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