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Activation of silent gene cluster

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https://www.readbyqxmd.com/read/28143937/screen-for-reactivation-of-mecp2-on-the-inactive-x-chromosome-identifies-the-bmp-tgf-%C3%AE-superfamily-as-a-regulator-of-xist-expression
#1
Smitha Sripathy, Vid Leko, Robin L Adrianse, Taylor Loe, Eric J Foss, Emily Dalrymple, Uyen Lao, Tonibelle Gatbonton-Schwager, Kelly T Carter, Bernhard Payer, Patrick J Paddison, William M Grady, Jeannie T Lee, Marisa S Bartolomei, Antonio Bedalov
Rett syndrome (RS) is a debilitating neurological disorder affecting mostly girls with heterozygous mutations in the gene encoding the methyl-CpG-binding protein MeCP2 on the X chromosome. Because restoration of MeCP2 expression in a mouse model reverses neurologic deficits in adult animals, reactivation of the wild-type copy of MeCP2 on the inactive X chromosome (Xi) presents a therapeutic opportunity in RS. To identify genes involved in MeCP2 silencing, we screened a library of 60,000 shRNAs using a cell line with a MeCP2 reporter on the Xi and found 30 genes clustered in seven functional groups...
January 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28103011/discovery-of-a-phosphonoacetic-acid-derived-natural-product-by-pathway-refactoring
#2
Todd S Freestone, Kou-San Ju, Bin Wang, Huimin Zhao
The activation of silent natural product gene clusters is a synthetic biology problem of great interest. As the rate at which gene clusters are identified outpaces the discovery rate of new molecules, this unknown chemical space is rapidly growing, as too are the rewards for developing technologies to exploit it. One class of natural products that has been underrepresented is phosphonic acids, which have important medical and agricultural uses. Hundreds of phosphonic acid biosynthetic gene clusters have been identified encoding for unknown molecules...
January 23, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28062460/large-scale-transposition-mutagenesis-of-streptomyces-coelicolor-identifies-hundreds-of-genes-influencing-antibiotic-biosynthesis
#3
Zhong Xu, Yemin Wang, Keith F Chater, Hong-Yu Ou, H Howard Xu, Zixin Deng, Meifeng Tao
: Gram-positive Streptomyces bacteria produce thousands of bioactive secondary metabolites including antibiotics. To systematically investigate genes affecting secondary metabolism, we developed a hyperactive transposase-based Tn5 transposition system and employed it to mutagenize the model species Streptomyces coelicolor, leading to the identification of 51,443 transposition insertions. These insertions were distributed randomly along the chromosome except for some preferred regions associated with relatively low GC content in the chromosomal core...
January 6, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/27981234/coordinate-regulation-of-antimycin-and-candicidin-biosynthesis
#4
Thomas C McLean, Paul A Hoskisson, Ryan F Seipke
Streptomyces species produce an incredible array of high-value specialty chemicals and medicinal therapeutics. A single species typically harbors ~30 biosynthetic pathways, but only a few them are expressed in the laboratory; thus, poor understanding of how natural-product biosynthesis is regulated is a major bottleneck in drug discovery. Antimycins are a large family of anticancer compounds widely produced by Streptomyces species, and their regulation is atypical compared to that of most other natural products...
November 2016: MSphere
https://www.readbyqxmd.com/read/27730337/stress-driven-discovery-of-a-cryptic-antibiotic-produced-by-streptomyces-sp-wu20-from-kueishantao-hydrothermal-vent-with-an-integrated-metabolomics-strategy
#5
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
https://www.readbyqxmd.com/read/27695614/expression-profile-of-developmentally-important-genes-in-preand-peri-implantation-goat-embryos-produced-in-vitro
#6
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
https://www.readbyqxmd.com/read/27621770/chromatin-boundary-elements-organize-genomic-architecture-and-developmental-gene-regulation-in-drosophila-hox-clusters
#7
REVIEW
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
https://www.readbyqxmd.com/read/27618884/new-deferoxamine-glycoconjugates-produced-upon-overexpression-of-pathway-specific-regulatory-gene-in-the-marine-sponge-derived-streptomyces-albus-pva94-07
#8
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...
August 27, 2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/27605017/discovery-of-unusual-biaryl-polyketides-by-activation-of-a-silent-streptomyces-venezuelae-biosynthetic-gene-cluster
#9
Anyarat Thanapipatsiri, Juan Pablo Gomez-Escribano, Lijiang Song, Maureen J Bibb, Mahmoud Al-Bassam, Govind Chandra, Arinthip Thamchaipenet, Gregory L Challis, Mervyn J 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, which we named venemycin, and potentially halogenated derivatives, contains 16 genes including one-vemR-that encodes a transcriptional activator of the large ATP-binding LuxR-like (LAL) family...
November 17, 2016: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/27576366/antibiotic-dialogues-induction-of-silent-biosynthetic-gene-clusters-by-exogenous-small-molecules
#10
REVIEW
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...
January 2017: FEMS Microbiology Reviews
https://www.readbyqxmd.com/read/27548260/kdmb-a-jumonji-histone-h3-demethylase-regulates-genome-wide-h3k4-trimethylation-and-is-required-for-normal-induction-of-secondary-metabolism-in-aspergillus-nidulans
#11
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
https://www.readbyqxmd.com/read/27487216/operation-of-a-homeostatic-sleep-switch
#12
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
https://www.readbyqxmd.com/read/27438486/native-and-engineered-promoters-in-natural-product-discovery
#13
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
https://www.readbyqxmd.com/read/27437574/structural-organization-of-the-inactive-x-chromosome-in-the-mouse
#14
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
https://www.readbyqxmd.com/read/27425419/intertwining-nutrient-sensory-networks-and-the-control-of-antibiotic-production-in-streptomyces
#15
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
https://www.readbyqxmd.com/read/27367535/mapping-the-trimethoprim-induced-secondary-metabolome-of-burkholderia-thailandensis
#16
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
https://www.readbyqxmd.com/read/27234993/hemoglobins-as-new-players-in-multiple-sclerosis-metabolic-and-immune-aspects
#17
REVIEW
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
https://www.readbyqxmd.com/read/27129958/influence-of-niche-specific-nutrients-on-secondary-metabolism-in-vibrionaceae
#18
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
https://www.readbyqxmd.com/read/27100123/development-of-a-synthetic-oxytetracycline-inducible-expression-system-for-streptomycetes-using-de-novo-characterized-genetic-parts
#19
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
https://www.readbyqxmd.com/read/26831707/enhancing-nonribosomal-peptide-biosynthesis-in-filamentous-fungi
#20
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
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