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基于玫瑰孢链霉菌 DNA 甲基组学鉴定和环境胁迫抗性新型调控因子 TagR 的特性分析

Identification and Characterization of a New Regulator, TagR, for Environmental Stress Resistance Based on the DNA Methylome of Streptomyces roseosporus.

机构信息

First Affiliated Hospital and Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine, Hangzhou, China.

Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering, Institute of Pharmaceutical Biotechnology, Hangzhou, China.

出版信息

Microbiol Spectr. 2023 Jun 15;11(3):e0038023. doi: 10.1128/spectrum.00380-23. Epub 2023 May 8.

DOI:10.1128/spectrum.00380-23
PMID:37154757
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10269677/
Abstract

DNA methylation is a defense that microorganisms use against extreme environmental stress, and improving resistance against environmental stress is essential for industrial actinomycetes. However, research on strain optimization utilizing DNA methylation for breakthroughs is rare. Based on DNA methylome analysis and KEGG pathway assignment in Streptomyces roseosporus, we discovered an environmental stress resistance regulator, TagR. A series of and experiments identified TagR as a negative regulator, and it is the first reported regulator of the wall teichoic acid (WTA) ABC transport system. Further study showed that TagR had a positive self-regulatory loop and m4C methylation in the promoter improved its expression. The Δ mutant exhibited better hyperosmotic resistance and higher decanoic acid tolerance than the wild type, which led to a 100% increase in the yield of daptomycin. Moreover, enhancing the expression of the WTA transporter resulted in better osmotic stress resistance in Streptomyces lividans TK24, indicating the potential for wide application of the TagR-WTA transporter regulatory pathway. This research confirmed the feasibility and effectiveness of mining regulators of environmental stress resistance based on the DNA methylome, characterized the mechanism of TagR, and improved the resistance and daptomycin yield of strains. Furthermore, this research provides a new perspective on the optimization of industrial actinomycetes. This study established a novel strategy for screening regulators of environmental stress resistance based on the DNA methylome and discovered a new regulator, TagR. The TagR-WTA transporter regulatory pathway improved the resistance and antibiotic yield of strains and has the potential for wide application. Our research provides a new perspective on the optimization and reconstruction of industrial actinomycetes.

摘要

DNA 甲基化是微生物对抗极端环境胁迫的一种防御机制，提高对环境胁迫的抗性对于工业放线菌至关重要。然而，利用 DNA 甲基化进行菌株优化以实现突破的研究很少。基于玫瑰色链霉菌的 DNA 甲基组分析和 KEGG 途径分配，我们发现了一种环境胁迫抗性调节剂 TagR。一系列的敲除和过表达实验确定了 TagR 作为一个负调控因子，它是第一个报道的细胞壁磷壁酸（WTA）ABC 转运系统的调控因子。进一步的研究表明，TagR 具有正的自我调控环，启动子中的 m4C 甲基化提高了其表达。Δ突变体表现出比野生型更好的高渗抗性和更高的癸酸耐受性，导致达托霉素的产量增加了 100%。此外，增强 WTA 转运体的表达可提高变铅青链霉菌 TK24 的渗透压应激抗性，表明 TagR-WTA 转运体调控途径具有广泛的应用潜力。这项研究证实了基于 DNA 甲基组挖掘环境应激抗性调节剂的可行性和有效性，表征了 TagR 的作用机制，并提高了菌株的抗性和达托霉素产量。此外，这项研究为工业放线菌的优化提供了一个新的视角。本研究建立了一种基于 DNA 甲基组筛选环境应激抗性调节剂的新策略，发现了一个新的调节剂 TagR。TagR-WTA 转运体调控途径提高了菌株的抗性和抗生素产量，具有广泛的应用潜力。我们的研究为工业放线菌的优化和改造提供了一个新的视角。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8232/10269677/0d84cbac206b/spectrum.00380-23-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8232/10269677/6e6fffd94f1a/spectrum.00380-23-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8232/10269677/7367afc5fe2e/spectrum.00380-23-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8232/10269677/b905a6f767f7/spectrum.00380-23-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8232/10269677/b248c769f7c6/spectrum.00380-23-f004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8232/10269677/9dc45b929bf3/spectrum.00380-23-f005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8232/10269677/0d84cbac206b/spectrum.00380-23-f006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8232/10269677/6e6fffd94f1a/spectrum.00380-23-f001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8232/10269677/7367afc5fe2e/spectrum.00380-23-f002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8232/10269677/b905a6f767f7/spectrum.00380-23-f003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8232/10269677/b248c769f7c6/spectrum.00380-23-f004.jpg
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