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      Transcriptional Activation of Biosynthetic Gene Clusters in Filamentous Fungi

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          Abstract

          Filamentous fungi are highly productive cell factories, many of which are industrial producers of enzymes, organic acids, and secondary metabolites. The increasing number of sequenced fungal genomes revealed a vast and unexplored biosynthetic potential in the form of transcriptionally silent secondary metabolite biosynthetic gene clusters (BGCs). Various strategies have been carried out to explore and mine this untapped source of bioactive molecules, and with the advent of synthetic biology, novel applications, and tools have been developed for filamentous fungi. Here we summarize approaches aiming for the expression of endogenous or exogenous natural product BGCs, including synthetic transcription factors, assembly of artificial transcription units, gene cluster refactoring, fungal shuttle vectors, and platform strains.

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          We describe an isothermal, single-reaction method for assembling multiple overlapping DNA molecules by the concerted action of a 5' exonuclease, a DNA polymerase and a DNA ligase. First we recessed DNA fragments, yielding single-stranded DNA overhangs that specifically annealed, and then covalently joined them. This assembly method can be used to seamlessly construct synthetic and natural genes, genetic pathways and entire genomes, and could be a useful molecular engineering tool.
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            The advent of facile genome engineering using the bacterial RNA-guided CRISPR-Cas9 system in animals and plants is transforming biology. We review the history of CRISPR (clustered regularly interspaced palindromic repeat) biology from its initial discovery through the elucidation of the CRISPR-Cas9 enzyme mechanism, which has set the stage for remarkable developments using this technology to modify, regulate, or mark genomic loci in a wide variety of cells and organisms from all three domains of life. These results highlight a new era in which genomic manipulation is no longer a bottleneck to experiments, paving the way toward fundamental discoveries in biology, with applications in all branches of biotechnology, as well as strategies for human therapeutics. Copyright © 2014, American Association for the Advancement of Science.
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              Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression.

              Targeted gene regulation on a genome-wide scale is a powerful strategy for interrogating, perturbing, and engineering cellular systems. Here, we develop a method for controlling gene expression based on Cas9, an RNA-guided DNA endonuclease from a type II CRISPR system. We show that a catalytically dead Cas9 lacking endonuclease activity, when coexpressed with a guide RNA, generates a DNA recognition complex that can specifically interfere with transcriptional elongation, RNA polymerase binding, or transcription factor binding. This system, which we call CRISPR interference (CRISPRi), can efficiently repress expression of targeted genes in Escherichia coli, with no detectable off-target effects. CRISPRi can be used to repress multiple target genes simultaneously, and its effects are reversible. We also show evidence that the system can be adapted for gene repression in mammalian cells. This RNA-guided DNA recognition platform provides a simple approach for selectively perturbing gene expression on a genome-wide scale. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Bioeng Biotechnol
                Front Bioeng Biotechnol
                Front. Bioeng. Biotechnol.
                Frontiers in Bioengineering and Biotechnology
                Frontiers Media S.A.
                2296-4185
                15 July 2022
                2022
                : 10
                : 901037
                Affiliations
                [1] 1 Department of Molecular Microbiology , Groningen Biomolecular Sciences and Biotechnology Institute , University of Groningen , Groningen, Netherlands
                [2] 2 DSM Biotechnology Center , Delft, Netherlands
                [3] 3 Department of Synthetic Biology and Cell Engineering , Groningen Biomolecular Sciences and Biotechnology Institute , University of Groningen , Groningen, Netherlands
                Author notes

                Edited by: A. Pedro Gonçalves, National Cheng Kung University, Taiwan

                Reviewed by: Mario Andrea Marchisio, Tianjin University, China

                Kai Blin, Technical University of Denmark, Denmark

                Andy Bailey, University of Bristol, United Kingdom

                Wan Abd Al Qadr Imad Wan Mohtar, University of Malaya, Malaysia

                *Correspondence: Arnold J. M. Driessen, a.j.m.driessen@ 123456rug.nl
                [ † ]

                Present address: László Mózsik, Department Molecular Microbiology and Biotechnology, Institute of Biology, Leiden University, Leiden, Netherlands; Riccardo Iacovelli, Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, Netherlands

                This article was submitted to Synthetic Biology, a section of the journal Frontiers in Bioengineering and Biotechnology

                Article
                901037
                10.3389/fbioe.2022.901037
                9335490
                35910033
                39a90d0c-efcc-4b5a-b8a4-82e4b470c698
                Copyright © 2022 Mózsik, Iacovelli, Bovenberg and Driessen.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 March 2022
                : 17 June 2022
                Funding
                Funded by: Horizon 2020 , doi 10.13039/501100007601;
                Categories
                Bioengineering and Biotechnology
                Review

                secondary metabilites,biosynthetic gene cluster,synthetic biology,synthetic transcriptional regulators,fungal platform strains

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