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Elucidating the regulatory mechanism of Swi1 prion in global transcription and stress responses.

ABSTRACT: Transcriptional regulators are prevalent among identified prions in Saccharomyces cerevisiae, however, it is unclear how prions affect genome-wide transcription. We show here that the prion ([SWI⁺]) and mutant (swi1?) forms of Swi1, a subunit of the SWI/SNF chromatin-remodeling complex, confer dramatically distinct transcriptomic profiles. In [SWI⁺] cells, genes encoding for 34 transcription factors (TFs) and 24 Swi1-interacting proteins can undergo transcriptional modifications. Several TFs show enhanced aggregation in [SWI⁺] cells. Further analyses suggest that such alterations are key factors in specifying the transcriptomic signatures of [SWI⁺] cells. Interestingly, swi1? and [SWI⁺] impose distinct and oftentimes opposite effects on cellular functions. Translation-associated activities, in particular, are significantly reduced in swi1? cells. Although both swi1? and [SWI⁺] cells are similarly sensitive to thermal, osmotic and drought stresses, harmful, neutral or beneficial effects were observed for a panel of tested chemical stressors. Further analyses suggest that the environmental stress response (ESR) is mechanistically different between swi1? and [SWI⁺] cells-stress-inducible ESR (iESR) are repressed by [SWI⁺] but unchanged by swi1? while stress-repressible ESR (rESR) are induced by [SWI⁺] but repressed by swi1?. Our work thus demonstrates primarily gain-of-function outcomes through transcriptomic modifications by [SWI⁺] and highlights a prion-mediated regulation of transcription and phenotypes in yeast.

SUBMITTER: Du Z

PROVIDER: S-EPMC7736884 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Elucidating the regulatory mechanism of Swi1 prion in global transcription and stress responses.

Du Zhiqiang Z Regan Jeniece J Bartom Elizabeth E Wu Wei-Sheng WS Zhang Li L Goncharoff Dustin Kenneth DK Li Liming L

Scientific reports 20201214 1

Transcriptional regulators are prevalent among identified prions in Saccharomyces cerevisiae, however, it is unclear how prions affect genome-wide transcription. We show here that the prion ([SWI<sup>+</sup>]) and mutant (swi1∆) forms of Swi1, a subunit of the SWI/SNF chromatin-remodeling complex, confer dramatically distinct transcriptomic profiles. In [SWI<sup>+</sup>] cells, genes encoding for 34 transcription factors (TFs) and 24 Swi1-interacting proteins can undergo transcriptional modifica ...[more]

PMID: 33318504

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Project description:Identification of transcriptional regulatory elements in the GC-rich Streptomyces genome is essential for the production of novel biochemicals from secondary metabolite biosynthetic gene clusters (smBGCs). Despite many efforts to understand the regulation of transcription initiation in smBGCs, information on the regulation of transcription termination and posttranscriptional processing remains scarce. In this study, we identified the transcriptional regulatory elements in β-lactam antibiotic-producing Streptomyces clavuligerus ATCC 27064 by determining a total of 1,427 transcript 3'-end positions (TEPs) using the term-seq method. Termination of transcription was governed by three classes of TEPs, of which each displayed unique sequence features. The data integration with transcription start sites and transcriptome data generated 1,648 transcription units (TUs) and 610 transcription unit clusters (TUCs). TU architecture showed that the transcript abundance in TU isoforms of a TUC was potentially affected by the sequence context of their TEPs, suggesting that the regulatory elements of TEPs could control the transcription level in additional layers. We also identified TU features of a xenobiotic response element (XRE) family regulator and DUF397 domain-containing protein, particularly showing the abundance of bidirectional TEPs. Finally, we found that 189 noncoding TUs contained potential cis- and trans-regulatory elements that played a major role in regulating the 5' and 3' UTR. These findings highlight the role of transcriptional regulatory elements in transcription termination and posttranscriptional processing in Streptomyces sp.IMPORTANCEStreptomyces sp. is a great source of bioactive secondary metabolites, including antibiotics, antifungal agents, antiparasitic agents, immunosuppressant compounds, and other drugs. Secondary metabolites are synthesized via multistep conversions of the precursor molecules from primary metabolism, governed by multicomplex enzymes from secondary metabolite biosynthetic gene clusters. As their production is closely related with the growth phase and dynamic cellular status in response to various intra- and extracellular signals, complex regulatory systems tightly control the gene expressions related to secondary metabolism. In this study, we determined genome-wide transcript 3'-end positions and transcription units in the β-lactam antibiotic producer Streptomyces clavuligerus ATCC 27064 to elucidate the transcriptional regulatory elements in transcription termination and posttranscriptional processing by integration of multiomics data. These unique features, such as transcript 3'-end sequence, potential riboregulators, and potential 3'-untranslated region (UTR) cis-regulatory elements, can be potentially used to design engineering tools that can regulate the transcript abundance of genes for enhancing secondary metabolite production.

Project description:BackgroundKnowledge on the molecular targets of diseases and drugs is crucial for elucidating disease pathogenesis and mechanism of action of drugs, and for driving drug discovery and treatment formulation. In this regard, high-throughput gene transcriptional profiling has become a leading technology, generating whole-genome data on the transcriptional alterations caused by diseases or drug compounds. However, identifying direct gene targets, especially in the background of indirect (downstream) effects, based on differential gene expressions is difficult due to the complexity of gene regulatory network governing the gene transcriptional processes.ResultsIn this work, we developed a network analysis method, called DeltaNeTS+, for inferring direct gene targets of drugs and diseases from gene transcriptional profiles. DeltaNeTS+ uses a gene regulatory network model to identify direct perturbations to the transcription of genes using gene expression data. Importantly, DeltaNeTS+ is able to combine both steady-state and time-course expression profiles, as well as leverage information on the gene network structure. We demonstrated the power of DeltaNeTS+ in predicting gene targets using gene expression data in complex organisms, including Caenorhabditis elegans and human cell lines (T-cell and Calu-3). More specifically, in an application to time-course gene expression profiles of influenza A H1N1 (swine flu) and H5N1 (avian flu) infection, DeltaNeTS+ shed light on the key differences of dynamic cellular perturbations caused by the two influenza strains.ConclusionDeltaNeTS+ is a powerful network analysis tool for inferring gene targets from gene expression profiles. As demonstrated in the case studies, by incorporating available information on gene network structure, DeltaNeTS+ produces accurate predictions of direct gene targets from a small sample size (~ 10 s). Integrating static and dynamic expression data with transcriptional network structure extracted from genomic information, as enabled by DeltaNeTS+, is crucial toward personalized medicine, where treatments can be tailored to individual patients. DeltaNeTS+ can be freely downloaded from http://www.github.com/cabsel/deltanetsplus .

Dataset Information

Elucidating the regulatory mechanism of Swi1 prion in global transcription and stress responses.

Publications

Elucidating the regulatory mechanism of Swi1 prion in global transcription and stress responses.

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