State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
Genomics Proteomics Bioinformatics. 2023 Dec;21(6):1149-1162. doi: 10.1016/j.gpb.2022.09.002. Epub 2022 Sep 15.
Streptomycetes possess numerous gene clusters and the potential to produce a large amount of natural products. Histone deacetylase (HDAC) inhibitors play an important role in the regulation of histone modifications in fungi, but their roles in prokaryotes remain poorly understood. Here, we investigated the global effects of the HDAC inhibitor, sodium butyrate (SB), on marine-derived Streptomycesolivaceus FXJ 8.021, particularly focusing on the activation of secondary metabolite biosynthesis. The antiSMASH analysis revealed 33 secondary metabolite biosynthetic gene clusters (BGCs) in strain FXJ 8.021, among which the silent lobophorin BGC was activated by SB. Transcriptomic data showed that the expression of genes involved in lobophorin biosynthesis (ge00097-ge00139) and CoA-ester formation (e.g., ge02824), as well as the glycolysis/gluconeogenesis pathway (e.g., ge01661), was significantly up-regulated in the presence of SB. Intracellular CoA-ester analysis confirmed that SB triggered the biosynthesis of CoA-ester, thereby increasing the precursor supply for lobophorin biosynthesis. Further acetylomic analysis revealed that the acetylation levels on 218 sites of 190 proteins were up-regulated and those on 411 sites of 310 proteins were down-regulated. These acetylated proteins were particularly enriched in transcriptional and translational machinery components (e.g., elongation factor GE04399), and their correlations with the proteins involved in lobophorin biosynthesis were established by protein-protein interaction network analysis, suggesting that SB might function via a complex hierarchical regulation to activate the expression of lobophorin BGC. These findings provide solid evidence that acetylated proteins triggered by SB could affect the expression of genes involved in the biosynthesis of primary and secondary metabolites in prokaryotes.
链霉菌拥有众多基因簇，有潜力产生大量天然产物。组蛋白去乙酰化酶 (HDAC) 抑制剂在真菌中组蛋白修饰的调控中起着重要作用，但它们在原核生物中的作用仍知之甚少。在这里，我们研究了组蛋白去乙酰化酶抑制剂丁酸钠 (SB) 对海洋来源的链霉菌 FXJ 8.021 的全局影响，特别是关注次生代谢产物生物合成的激活。antiSMASH 分析显示菌株 FXJ 8.021 中存在 33 个次生代谢产物生物合成基因簇 (BGC)，其中沉默的 lobophorin BGC 被 SB 激活。转录组数据显示，参与 lobophorin 生物合成 (ge00097-ge00139) 和 CoA-ester 形成 (如 ge02824) 以及糖酵解/糖异生途径 (如 ge01661) 的基因表达显著上调在 SB 的存在下。细胞内 CoA-ester 分析证实 SB 触发了 CoA-ester 的生物合成，从而增加了 lobophorin 生物合成的前体供应。进一步的乙酰化组学分析表明，190 个蛋白的 218 个位点的乙酰化水平上调，310 个蛋白的 411 个位点的乙酰化水平下调。这些乙酰化蛋白特别富含转录和翻译机制成分（如伸长因子 GE04399），并且通过蛋白质-蛋白质相互作用网络分析与参与 lobophorin 生物合成的蛋白质建立了相关性，表明 SB 可能通过复杂的层次调节来激活 lobophorin BGC 的表达。这些发现为乙酰化蛋白被 SB 触发可以影响原核生物中参与初级和次级代谢产物生物合成的基因表达提供了确凿的证据。
