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System-level understanding of gene expression and regulation for engineering secondary metabolite production in Streptomyces

Abstract

The gram-positive bacterium, Streptomyces, is noticed for its ability to produce a wide array of pharmaceutically active compounds through secondary metabolism. To discover novel bioactive secondary metabolites and increase the production, Streptomyces species have been extensively studied for the past decades. Among the cellular components, RNA molecules play important roles as the messengers for gene expression and diverse regulations taking place at the RNA level. Thus, the analysis of RNA-level regulation is critical to understanding the regulation of Streptomyces’ metabolism and secondary metabolite production. A dramatic advance in Streptomyces research was made recently, by exploiting high-throughput technology to systematically understand RNA levels. In this review, we describe the current status of the system-wide investigation of Streptomyces in terms of RNA, toward expansion of its genetic potential for secondary metabolite synthesis.

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References

  1. Al-Bassam MM, Bibb MJ, Bush MJ, Chandra G, Buttner MJ (2014) Response regulator heterodimer formation controls a key stage in Streptomyces development. PLoS Genet 10:e1004554. https://doi.org/10.1371/journal.pgen.1004554

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Alam MT, Merlo ME, Consortium S, Hodgson DA, Wellington EM, Takano E, Breitling R (2010) Metabolic modeling and analysis of the metabolic switch in Streptomyces coelicolor. BMC Genomics 11:202. https://doi.org/10.1186/1471-2164-11-202

    CAS  Article  Google Scholar 

  3. Anné J, Vrancken K, Van Mellaert L, Van Impe J, Bernaerts K (2014) Protein secretion biotechnology in Gram-positive bacteria with special emphasis on Streptomyces lividans. Biochim Biophys Acta 1843:1750–1761. https://doi.org/10.1016/j.bbamcr.2013.12.023

    CAS  Article  PubMed  Google Scholar 

  4. Balleza E, López-Bojorquez LN, Martínez-Antonio A, Resendis-Antonio O, Lozada-Chávez I, Balderas-Martínez YI, Encarnación S, Collado-Vides J (2009) Regulation by transcription factors in bacteria: beyond description. FEMS Microbiol Rev 33:133–151. https://doi.org/10.1111/j.1574-6976.2008.00145.x

    CAS  Article  PubMed  Google Scholar 

  5. Bauer JS, Fillinger S, Förstner K, Herbig A, Jones AC, Flinspach K, Sharma C, Gross H, Nieselt K, Apel AK (2017) dRNA-seq transcriptional profiling of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis NRRL18488 and general analysis of the transcriptome. RNA Biol 14:1617–1626. https://doi.org/10.1080/15476286.2017.1341020

    Article  PubMed  PubMed Central  Google Scholar 

  6. Beck HJ, Moll I (2018) Leaderless mRNAs in the spotlight: ancient but not outdated! Microbiol Spectr. https://doi.org/10.1128/microbiolspec.RWR-0016-2017

    Article  PubMed  Google Scholar 

  7. Bentley DR, Balasubramanian S, Swerdlow HP, Smith GP, Milton J, Brown CG, Hall KP, Evers DJ, Barnes CL, Bignell HR, Boutell JM, Bryant J, Carter RJ, Keira Cheetham R, Cox AJ, Ellis DJ, Flatbush MR, Gormley NA, Humphray SJ, Irving LJ, Karbelashvili MS, Kirk SM, Li H, Liu X, Maisinger KS, Murray LJ, Obradovic B, Ost T, Parkinson ML, Pratt MR, Rasolonjatovo IM, Reed MT, Rigatti R, Rodighiero C, Ross MT, Sabot A, Sankar SV, Scally A, Schroth GP, Smith ME, Smith VP, Spiridou A, Torrance PE, Tzonev SS, Vermaas EH, Walter K, Wu X, Zhang L, Alam MD, Anastasi C, Aniebo IC, Bailey DM, Bancarz IR, Banerjee S, Barbour SG, Baybayan PA, Benoit VA, Benson KF, Bevis C, Black PJ, Boodhun A, Brennan JS, Bridgham JA, Brown RC, Brown AA, Buermann DH, Bundu AA, Burrows JC, Carter NP, Castillo N, Chiara ECM, Chang S, Neil Cooley R, Crake NR, Dada OO, Diakoumakos KD, Dominguez-Fernandez B, Earnshaw DJ, Egbujor UC, Elmore DW, Etchin SS, Ewan MR, Fedurco M, Fraser LJ, Fuentes Fajardo KV, Scott Furey W, George D, Gietzen KJ, Goddard CP, Golda GS, Granieri PA, Green DE, Gustafson DL, Hansen NF, Harnish K, Haudenschild CD, Heyer NI, Hims MM, Ho JT, Horgan AM, Hoschler K, Hurwitz S, Ivanov DV, Johnson MQ, James T, Huw Jones TA, Kang GD, Kerelska TH, Kersey AD, Khrebtukova I, Kindwall AP, Kingsbury Z, Kokko-Gonzales PI, Kumar A, Laurent MA, Lawley CT, Lee SE, Lee X, Liao AK, Loch JA, Lok M, Luo S, Mammen RM, Martin JW, McCauley PG, McNitt P, Mehta P, Moon KW, Mullens JW, Newington T, Ning Z, Ling Ng B, Novo SM, O'Neill MJ, Osborne MA, Osnowski A, Ostadan O, Paraschos LL, Pickering L, Pike AC, Pike AC, Chris Pinkard D, Pliskin DP, Podhasky J, Quijano VJ, Raczy C, Rae VH, Rawlings SR, Chiva Rodriguez A, Roe PM, Rogers J, Rogert Bacigalupo MC, Romanov N, Romieu A, Roth RK, Rourke NJ, Ruediger ST, Rusman E, Sanches-Kuiper RM, Schenker MR, Seoane JM, Shaw RJ, Shiver MK, Short SW, Sizto NL, Sluis JP, Smith MA, Ernest Sohna Sohna J, Spence EJ, Stevens K, Sutton N, Szajkowski L, Tregidgo CL, Turcatti G, Vandevondele S, Verhovsky Y, Virk SM, Wakelin S, Walcott GC, Wang J, Worsley GJ, Yan J, Yau L, Zuerlein M, Rogers J, Mullikin JC, Hurles ME, McCooke NJ, West JS, Oaks FL, Lundberg PL, Klenerman D, Durbin R, Smith AJ (2008) Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456:53–59. https://doi.org/10.1038/nature07517

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Bentley SD, Chater KF, Cerdeño-Tárraga AM, Challis GL, Thomson NR, James KD, Harris DE, Quail MA, Kieser H, Harper D, Bateman A, Brown S, Chandra G, Chen CW, Collins M, Cronin A, Fraser A, Goble A, Hidalgo J, Hornsby T, Howarth S, Huang CH, Kieser T, Larke L, Murphy L, Oliver K, O'Neil S, Rabbinowitsch E, Rajandream MA, Rutherford K, Rutter S, Seeger K, Saunders D, Sharp S, Squares R, Squares S, Taylor K, Warren T, Wietzorrek A, Woodward J, Barrell BG, Parkhill J, Hopwood DA (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147. https://doi.org/10.1038/417141a

    Article  PubMed  Google Scholar 

  9. Bérdy J (2005) Bioactive microbial metabolites. J Antibiot (Tokyo) 58:1–26. https://doi.org/10.1038/ja.2005.1

    Article  Google Scholar 

  10. Bibb MJ (2005) Regulation of secondary metabolism in streptomycetes. Curr Opin Microbiol 8:208–215. https://doi.org/10.1016/j.mib.2005.02.016

    CAS  Article  PubMed  Google Scholar 

  11. Bikard D, Jiang W, Samai P, Hochschild A, Zhang F, Marraffini LA (2013) Programmable repression and activation of bacterial gene expression using an engineered CRISPR-Cas system. Nucleic Acids Res 41:7429–7437. https://doi.org/10.1093/nar/gkt520

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. Blin K, Shaw S, Steinke K, Villebro R, Ziemert N, Lee SY, Medema MH, Weber T (2019) antiSMASH 5.0: updates to the secondary metabolite genome mining pipeline. Nucleic Acids Res 47:W81–W87. https://doi.org/10.1093/nar/gkz310

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. Browning DF, Busby SJ (2004) The regulation of bacterial transcription initiation. Nat Rev Microbiol 2:57–65. https://doi.org/10.1038/nrmicro787

    CAS  Article  PubMed  Google Scholar 

  14. Bursy J, Kuhlmann AU, Pittelkow M, Hartmann H, Jebbar M, Pierik AJ, Bremer E (2008) Synthesis and uptake of the compatible solutes ectoine and 5-hydroxyectoine by Streptomyces coelicolor A3(2) in response to salt and heat stresses. Appl Environ Microbiol 74:7286–7296. https://doi.org/10.1128/AEM.00768-08

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. Bush MJ, Bibb MJ, Chandra G, Findlay KC, Buttner MJ (2013) Genes required for aerial growth, cell division, and chromosome segregation are targets of WhiA before sporulation in Streptomyces venezuelae. mBio 4:e00684–e1613. https://doi.org/10.1128/mBio.00684-13

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Bush MJ, Chandra G, Al-Bassam MM, Findlay KC, Buttner MJ (2019) BldC delays entry into development to produce a sustained period of vegetative growth in Streptomyces venezuelae. mBio. https://doi.org/10.1128/mBio.02812-18

    Article  PubMed  PubMed Central  Google Scholar 

  17. Bush MJ, Chandra G, Bibb MJ, Findlay KC, Buttner MJ (2016) Genome-wide chromatin immunoprecipitation sequencing analysis shows that whib is a transcription factor that cocontrols its regulon with WhiA to initiate developmental cell division in Streptomyces. mBio 7:e00523–e1516. https://doi.org/10.1128/mBio.00523-16

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. Bush MJ, Chandra G, Findlay KC, Buttner MJ (2017) Multi-layered inhibition of Streptomyces development: BldO is a dedicated repressor of whiB. Mol Microbiol 104:700–711. https://doi.org/10.1111/mmi.13663

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Chakraburtty R, Bibb M (1997) The ppGpp synthetase gene (relA) of Streptomyces coelicolor A3(2) plays a conditional role in antibiotic production and morphological differentiation. J Bacteriol 179:5854–5861. https://doi.org/10.1128/jb.179.18.5854-5861.1997

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. Challis GL, Hopwood DA (2003) Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species. Proc Natl Acad Sci USA 100(Suppl 2):14555–14561. https://doi.org/10.1073/pnas.1934677100

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Charaniya S, Mehra S, Lian W, Jayapal KP, Karypis G, Hu WS (2007) Transcriptome dynamics-based operon prediction and verification in Streptomyces coelicolor. Nucleic Acids Res 35:7222–7236. https://doi.org/10.1093/nar/gkm501

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Chen Y, Wendt-Pienkowski E, Shen B (2008) Identification and utility of FdmR1 as a Streptomyces antibiotic regulatory protein activator for fredericamycin production in Streptomyces griseus ATCC 49344 and heterologous hosts. J Bacteriol 190:5587–5596. https://doi.org/10.1128/JB.00592-08

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Cho BK, Zengler K, Qiu Y, Park YS, Knight EM, Barrett CL, Gao Y, Palsson BO (2009) The transcription unit architecture of the Escherichia coli genome. Nat Biotechnol 27:1043–1049. https://doi.org/10.1038/nbt.1582

    CAS  Article  PubMed  Google Scholar 

  24. Cortes T, Schubert OT, Rose G, Arnvig KB, Comas I, Aebersold R, Young DB (2013) Genome-wide mapping of transcriptional start sites defines an extensive leaderless transcriptome in Mycobacterium tuberculosis. Cell Rep 5:1121–1131. https://doi.org/10.1016/j.celrep.2013.10.031

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Crack JC, Munnoch J, Dodd EL, Knowles F, Al Bassam MM, Kamali S, Holland AA, Cramer SP, Hamilton CJ, Johnson MK, Thomson AJ, Hutchings MI, Le Brun NE (2015) NsrR from Streptomyces coelicolor is a nitric oxide-sensing [4Fe-4S] cluster protein with a specialized regulatory function. J Biol Chem 290:12689–12704. https://doi.org/10.1074/jbc.M115.643072

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. Crawford DL (1978) Lignocellulose decomposition by selected Streptomyces strains. Appl Environ Microbiol 35:1041–1045

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Crick F (1970) Central dogma of molecular biology. Nature 227:561–563. https://doi.org/10.1038/227561a0

    CAS  Article  PubMed  Google Scholar 

  28. Dar D, Shamir M, Mellin JR, Koutero M, Stern-Ginossar N, Cossart P, Sorek R (2016) Term-seq reveals abundant ribo-regulation of antibiotics resistance in bacteria. Science 352:aad9822. https://doi.org/10.1126/science.aad9822

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. de Groot A, Roche D, Fernandez B, Ludanyi M, Cruveiller S, Pignol D, Vallenet D, Armengaud J, Blanchard L (2014) RNA sequencing and proteogenomics reveal the importance of leaderless mRNAs in the radiation-tolerant bacterium Deinococcus deserti. Genome Biol Evol 6:932–948. https://doi.org/10.1093/gbe/evu069

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Demain AL (1999) Pharmaceutically active secondary metabolites of microorganisms. Appl Microbiol Biotechnol 52:455–463. https://doi.org/10.1007/s002530051546

    CAS  Article  PubMed  Google Scholar 

  31. Engel F, Ossipova E, Jakobsson PJ, Vockenhuber MP, Suess B (2019) sRNA scr5239 involved in feedback loop regulation of Streptomyces coelicolor central metabolism. Front Microbiol 10:3121. https://doi.org/10.3389/fmicb.2019.03121

    Article  PubMed  Google Scholar 

  32. Fan H, Conn AB, Williams PB, Diggs S, Hahm J, Gamper HB Jr, Hou YM, O'Leary SE, Wang Y, Blaha GM (2017) Transcription-translation coupling: direct interactions of RNA polymerase with ribosomes and ribosomal subunits. Nucleic Acids Res 45:11043–11055. https://doi.org/10.1093/nar/gkx719

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. Ferguson NL, Peña-Castillo L, Moore MA, Bignell DR, Tahlan K (2016) Proteomics analysis of global regulatory cascades involved in clavulanic acid production and morphological development in Streptomyces clavuligerus. J Ind Microbiol Biotechnol 43:537–555. https://doi.org/10.1007/s10295-016-1733-y

    CAS  Article  PubMed  Google Scholar 

  34. Flärdh K, Buttner MJ (2009) Streptomyces morphogenetics: dissecting differentiation in a filamentous bacterium. Nat Rev Microbiol 7:36–49. https://doi.org/10.1038/nrmicro1968

    CAS  Article  PubMed  Google Scholar 

  35. Fu J, Qin R, Zong G, Liu C, Kang N, Zhong C, Cao G (2019) The CagRS two-component system regulates clavulanic acid metabolism via multiple pathways in Streptomyces clavuligerus F613–1. Front Microbiol 10:244. https://doi.org/10.3389/fmicb.2019.00244

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gehrke EJ, Zhang X, Pimentel-Elardo SM, Johnson AR, Rees CA, Jones SE, Hindra GSS, Turvey S, Boursalie S, Hill JE, Carlson EE, Nodwell JR, Elliot MA (2019) Silencing cryptic specialized metabolism in Streptomyces by the nucleoid-associated protein Lsr2. Elife. https://doi.org/10.7554/eLife.47691

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hallberg ZF, Su Y, Kitto RZ, Hammond MC (2017) Engineering and in vivo applications of riboswitches. Annu Rev Biochem 86:515–539. https://doi.org/10.1146/annurev-biochem-060815-014628

    CAS  Article  PubMed  Google Scholar 

  38. Hamed MB, Anné J, Karamanou S, Economou A (2018) Streptomyces protein secretion and its application in biotechnology. FEMS Microbiol Lett. https://doi.org/10.1093/femsle/fny250

    Article  PubMed  Google Scholar 

  39. Higo A, Hara H, Horinouchi S, Ohnishi Y (2012) Genome-wide distribution of AdpA, a global regulator for secondary metabolism and morphological differentiation in Streptomyces, revealed the extent and complexity of the AdpA regulatory network. DNA Res 19:259–273. https://doi.org/10.1093/dnares/dss010

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Hirakata T, Urabe H, Sugita T (2019) Phosphoproteomic and proteomic profiling of serine/threonine protein kinase PkaE of Streptomyces coelicolor A3(2) and its role in secondary metabolism and morphogenesis. Biosci Biotechnol Biochem 83:1843–1850. https://doi.org/10.1080/09168451.2019.1618698

    CAS  Article  PubMed  Google Scholar 

  41. Hopwood DA, Sherman DH (1990) Molecular genetics of polyketides and its comparison to fatty acid biosynthesis. Annu Rev Genet 24:37–66. https://doi.org/10.1146/annurev.ge.24.120190.000345

    CAS  Article  PubMed  Google Scholar 

  42. Huang H, Zheng G, Jiang W, Hu H, Lu Y (2015) One-step high-efficiency CRISPR/Cas9-mediated genome editing in Streptomyces. Acta Biochim Biophys Sin (Shanghai) 47:231–243. https://doi.org/10.1093/abbs/gmv007

    CAS  Article  Google Scholar 

  43. Hwang S, Lee N, Jeong Y, Lee Y, Kim W, Cho S, Palsson BO, Cho BK (2019) Primary transcriptome and translatome analysis determines transcriptional and translational regulatory elements encoded in the Streptomyces clavuligerus genome. Nucleic Acids Res 47:6114–6129. https://doi.org/10.1093/nar/gkz471

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. Ingolia NT, Ghaemmaghami S, Newman JR, Weissman JS (2009) Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324:218–223. https://doi.org/10.1126/science.1168978

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Ishigaki Y, Akanuma G, Yoshida M, Horinouchi S, Kosono S, Ohnishi Y (2017) Protein acetylation involved in streptomycin biosynthesis in Streptomyces griseus. J Proteomics 155:63–72. https://doi.org/10.1016/j.jprot.2016.12.006

    CAS  Article  PubMed  Google Scholar 

  46. Jayapal KP, Philp RJ, Kok YJ, Yap MG, Sherman DH, Griffin TJ, Hu WS (2008) Uncovering genes with divergent mRNA-protein dynamics in Streptomyces coelicolor. PLoS ONE 3:e2097. https://doi.org/10.1371/journal.pone.0002097

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Jeong Y, Kim JN, Kim MW, Bucca G, Cho S, Yoon YJ, Kim BG, Roe JH, Kim SC, Smith CP, Cho BK (2016) The dynamic transcriptional and translational landscape of the model antibiotic producer Streptomyces coelicolor A3(2). Nat Commun 7:11605. https://doi.org/10.1038/ncomms11605

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Johnson DS, Mortazavi A, Myers RM, Wold B (2007) Genome-wide mapping of in vivo protein-DNA interactions. Science 316:1497–1502. https://doi.org/10.1126/science.1141319

    CAS  Article  PubMed  Google Scholar 

  49. Kaberdina AC, Szaflarski W, Nierhaus KH, Moll I (2009) An unexpected type of ribosomes induced by kasugamycin: a look into ancestral times of protein synthesis? Mol Cell 33:227–236. https://doi.org/10.1016/j.molcel.2008.12.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Kim JN, Jeong Y, Yoo JS, Roe JH, Cho BK, Kim BG (2015) Genome-scale analysis reveals a role for NdgR in the thiol oxidative stress response in Streptomyces coelicolor. BMC Genom 16:116. https://doi.org/10.1186/s12864-015-1311-0

    CAS  Article  Google Scholar 

  51. Kim MW, Lee BR, You S, Kim EJ, Kim JN, Song E, Yang YH, Hwang D, Kim BG (2018) Transcriptome analysis of wild-type and afsS deletion mutant strains identifies synergistic transcriptional regulator of afsS for a high antibiotic-producing strain of Streptomyces coelicolor A3(2). Appl Microbiol Biotechnol 102:3243–3253. https://doi.org/10.1007/s00253-018-8838-3

    CAS  Article  PubMed  Google Scholar 

  52. Le Maréchal P, Decottignies P, Marchand CH, Degrouard J, Jaillard D, Dulermo T, Froissard M, Smirnov A, Chapuis V, Virolle MJ (2013) Comparative proteomic analysis of Streptomyces lividans wild-type and ppk mutant strains reveals the importance of storage lipids for antibiotic biosynthesis. Appl Environ Microbiol 79:5907–5917. https://doi.org/10.1128/AEM.02280-13

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Lee JH, Yoo JS, Kim Y, Kim JS, Lee EJ, Roe JH (2020) The WblC/WhiB7 transcription factor controls intrinsic resistance to translation-targeting antibiotics by altering ribosome composition. mBio. https://doi.org/10.1128/mBio.00625-20

    Article  PubMed  PubMed Central  Google Scholar 

  54. Lee N, Hwang S, Lee Y, Cho S, Palsson B, Cho BK (2019) Synthetic biology tools for novel secondary metabolite discovery in Streptomyces. J Microbiol Biotechnol 29:667–686. https://doi.org/10.4014/jmb.1904.04015

    CAS  Article  PubMed  Google Scholar 

  55. Lee N, Kim W, Chung J, Lee Y, Cho S, Jang KS, Kim SC, Palsson B, Cho BK (2020) Iron competition triggers antibiotic biosynthesis in Streptomyces coelicolor during coculture with Myxococcus xanthus. ISME J. https://doi.org/10.1038/s41396-020-0594-6

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lee N, Kim W, Hwang S, Lee Y, Cho S, Palsson B, Cho BK (2020) Thirty complete Streptomyces genome sequences for mining novel secondary metabolite biosynthetic gene clusters. Sci Data 7:55. https://doi.org/10.1038/s41597-020-0395-9

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. Lee Y, Lee N, Jeong Y, Hwang S, Kim W, Cho S, Palsson BO, Cho BK (2019) The transcription unit architecture of Streptomyces lividans TK24. Front Microbiol 10:2074. https://doi.org/10.3389/fmicb.2019.02074

    Article  PubMed  PubMed Central  Google Scholar 

  58. Li L, Wei K, Zheng G, Liu X, Chen S, Jiang W, Lu Y (2018) CRISPR-Cpf1-assisted multiplex genome editing and transcriptional repression in Streptomyces. Appl Environ Microbiol. https://doi.org/10.1128/AEM.00827-18

    Article  PubMed  PubMed Central  Google Scholar 

  59. Li X, Wang J, Li S, Ji J, Wang W, Yang K (2015) ScbR- and ScbR2-mediated signal transduction networks coordinate complex physiological responses in Streptomyces coelicolor. Sci Rep 5:14831. https://doi.org/10.1038/srep14831

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Li Y, Kong L, Shen J, Wang Q, Liu Q, Yang W, Deng Z, You D (2019) Characterization of the positive SARP family regulator PieR for improving piericidin A1 production in Streptomyces piomogeues var. Hangzhouwanensis Synth Syst Biotechnol 4:16–24. https://doi.org/10.1016/j.synbio.2018.12.002

    Article  PubMed  Google Scholar 

  61. Liao G, Xie L, Li X, Cheng Z, Xie J (2014) Unexpected extensive lysine acetylation in the trump-card antibiotic producer Streptomyces roseosporus revealed by proteome-wide profiling. J Proteomics 106:260–269. https://doi.org/10.1016/j.jprot.2014.04.017

    CAS  Article  PubMed  Google Scholar 

  62. Liu M, Zhang P, Zhu Y, Lu T, Wang Y, Cao G, Shi M, Chen XL, Tao M, Pang X (2019) Novel two-component system MacRS is a pleiotropic regulator that controls multiple morphogenic membrane protein genes in Streptomyces coelicolor. Appl Environ Microbiol. https://doi.org/10.1128/AEM.02178-18

    Article  PubMed  PubMed Central  Google Scholar 

  63. López-García MT, Yagüe P, González-Quiñónez N, Rioseras B, Manteca A (2018) The SCO4117 ECF sigma factor pleiotropically controls secondary metabolism and morphogenesis in Streptomyces coelicolor. Front Microbiol 9:312. https://doi.org/10.3389/fmicb.2018.00312

    Article  PubMed  PubMed Central  Google Scholar 

  64. Luo Y, Zhang L, Barton KW, Zhao H (2015) Systematic identification of a panel of strong constitutive promoters from Streptomyces albus. ACS Synth Biol 4:1001–1010. https://doi.org/10.1021/acssynbio.5b00016

    CAS  Article  PubMed  Google Scholar 

  65. Mohammad F, Woolstenhulme CJ, Green R, Buskirk AR (2016) Clarifying the translational pausing landscape in bacteria by ribosome profiling. Cell Rep 14:686–694. https://doi.org/10.1016/j.celrep.2015.12.073

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. Moll I, Hirokawa G, Kiel MC, Kaji A, Bläsi U (2004) Translation initiation with 70S ribosomes: an alternative pathway for leaderless mRNAs. Nucleic Acids Res 32:3354–3363. https://doi.org/10.1093/nar/gkh663

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Munnoch JT, Martinez MT, Svistunenko DA, Crack JC, Le Brun NE, Hutchings MI (2016) Characterization of a putative NsrR homologue in Streptomyces venezuelae reveals a new member of the Rrf2 superfamily. Sci Rep 6:31597. https://doi.org/10.1038/srep31597

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Ochi K (2007) From microbial differentiation to ribosome engineering. Biosci Biotechnol Biochem 71:1373–1386. https://doi.org/10.1271/bbb.70007

    CAS  Article  PubMed  Google Scholar 

  69. Ohnishi Y, Yamazaki H, Kato JY, Tomono A, Horinouchi S (2005) AdpA, a central transcriptional regulator in the A-factor regulatory cascade that leads to morphological development and secondary metabolism in Streptomyces griseus. Biosci Biotechnol Biochem 69:431–439. https://doi.org/10.1271/bbb.69.431

    CAS  Article  PubMed  Google Scholar 

  70. Papenfort K, Vogel J (2010) Regulatory RNA in bacterial pathogens. Cell Host Microbe 8:116–127. https://doi.org/10.1016/j.chom.2010.06.008

    CAS  Article  PubMed  Google Scholar 

  71. Paulus C, Rebets Y, Tokovenko B, Nadmid S, Terekhova LP, Myronovskyi M, Zotchev SB, Rückert C, Braig S, Zahler S, Kalinowski J, Luzhetskyy A (2017) New natural products identified by combined genomics-metabolomics profiling of marine Streptomyces sp. MP131–18. Sci Rep 7:42382. https://doi.org/10.1038/srep42382

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Payne GF, DelaCruz N, Coppella SJ (1990) Improved production of heterologous protein from Streptomyces lividans. Appl Microbiol Biotechnol 33:395–400. https://doi.org/10.1007/bf00176653

    CAS  Article  PubMed  Google Scholar 

  73. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, Lim WA (2013) Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152:1173–1183. https://doi.org/10.1016/j.cell.2013.02.022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. Ramisetty BC, Ghosh D, Roy Chowdhury M, Santhosh RS (2016) What Is the link between stringent response, endoribonuclease encoding type II toxin-antitoxin systems and persistence? Front Microbiol 7:1882. https://doi.org/10.3389/fmicb.2016.01882

    Article  PubMed  PubMed Central  Google Scholar 

  75. Schumacher MA, Zeng W, Findlay KC, Buttner MJ, Brennan RG, Tschowri N (2017) The Streptomyces master regulator BldD binds c-di-GMP sequentially to create a functional BldD2-(c-di-GMP)4 complex. Nucleic Acids Res 45:6923–6933. https://doi.org/10.1093/nar/gkx287

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. Sedlyarova N, Shamovsky I, Bharati BK, Epshtein V, Chen J, Gottesman S, Schroeder R, Nudler E (2016) sRNA-Mediated control of transcription termination in E. coli. Cell 167:111–121. https://doi.org/10.1016/j.cell.2016.09.004(e113)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. Seshasayee AS, Bertone P, Fraser GM, Luscombe NM (2006) Transcriptional regulatory networks in bacteria: from input signals to output responses. Curr Opin Microbiol 9:511–519. https://doi.org/10.1016/j.mib.2006.08.007

    CAS  Article  PubMed  Google Scholar 

  78. Shi Y, Pan C, Auckloo BN, Chen X, Chen CA, Wang K, Wu X, Ye Y, Wu B (2017) Stress-driven discovery of a cryptic antibiotic produced by Streptomyces sp. WU20 from Kueishantao hydrothermal vent with an integrated metabolomics strategy. Appl Microbiol Biotechnol 101:1395–1408. https://doi.org/10.1007/s00253-016-7823-y

    CAS  Article  PubMed  Google Scholar 

  79. Sidebottom AM, Johnson AR, Karty JA, Trader DJ, Carlson EE (2013) Integrated metabolomics approach facilitates discovery of an unpredicted natural product suite from Streptomyces coelicolor M145. ACS Chem Biol 8:2009–2016. https://doi.org/10.1021/cb4002798

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. Siu KH, Chen W (2019) Riboregulated toehold-gated gRNA for programmable CRISPR-Cas9 function. Nat Chem Biol 15:217–220. https://doi.org/10.1038/s41589-018-0186-1

    CAS  Article  PubMed  Google Scholar 

  81. Šmídová K, Ziková A, Pospíšil J, Schwarz M, Bobek J, Vohradsky J (2019) DNA mapping and kinetic modeling of the HrdB regulon in Streptomyces coelicolor. Nucleic Acids Res 47:621–633. https://doi.org/10.1093/nar/gky1018

    CAS  Article  PubMed  Google Scholar 

  82. Som NF, Heine D, Holmes N, Knowles F, Chandra G, Seipke RF, Hoskisson PA, Wilkinson B, Hutchings MI (2017) The MtrAB two-component system controls antibiotic production in Streptomyces coelicolor A3(2). Microbiology 163:1415–1419. https://doi.org/10.1099/mic.0.000524

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  83. Som NF, Heine D, Holmes NA, Munnoch JT, Chandra G, Seipke RF, Hoskisson PA, Wilkinson B, Hutchings MI (2017) The conserved actinobacterial two-component system MtrAB coordinates chloramphenicol production with sporulation in Streptomyces venezuelae NRRL B-65442. Front Microbiol 8:1145. https://doi.org/10.3389/fmicb.2017.01145

    Article  PubMed  PubMed Central  Google Scholar 

  84. Staroń A, Sofia HJ, Dietrich S, Ulrich LE, Liesegang H, Mascher T (2009) The third pillar of bacterial signal transduction: classification of the extracytoplasmic function (ECF) σ factor protein family. Mol Microbiol 74:557–581. https://doi.org/10.1111/j.1365-2958.2009.06870.x

    CAS  Article  PubMed  Google Scholar 

  85. Storz G, Vogel J, Wassarman KM (2011) Regulation by small RNAs in bacteria: expanding frontiers. Mol Cell 43:880–891. https://doi.org/10.1016/j.molcel.2011.08.022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. Taniguchi Y, Choi PJ, Li GW, Chen H, Babu M, Hearn J, Emili A, Xie XS (2010) Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells. Science 329:533–538. https://doi.org/10.1126/science.1188308

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. Tezuka T, Ohnishi Y (2014) Two glycine riboswitches activate the glycine cleavage system essential for glycine detoxification in Streptomyces griseus. J Bacteriol 196:1369–1376. https://doi.org/10.1128/JB.01480-13

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. Tong Y, Charusanti P, Zhang L, Weber T, Lee SY (2015) CRISPR-Cas9 based engineering of actinomycetal genomes. ACS Synth Biol 4:1020–1029. https://doi.org/10.1021/acssynbio.5b00038

    CAS  Article  PubMed  Google Scholar 

  89. Tran NT, Huang X, Hong HJ, Bush MJ, Chandra G, Pinto D, Bibb MJ, Hutchings MI, Mascher T, Buttner MJ (2019) Defining the regulon of genes controlled by σE, a key regulator of the cell envelope stress response in Streptomyces coelicolor. Mol Microbiol 112:461–481. https://doi.org/10.1111/mmi.14250

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. Traxler MF, Watrous JD, Alexandrov T, Dorrestein PC, Kolter R (2013) Interspecies interactions stimulate diversification of the Streptomyces coelicolor secreted metabolome. mBio. https://doi.org/10.1128/mBio.00459-13

    Article  PubMed  PubMed Central  Google Scholar 

  91. Tschowri N, Schumacher MA, Schlimpert S, Chinnam NB, Findlay KC, Brennan RG, Buttner MJ (2014) Tetrameric c-di-GMP mediates effective transcription factor dimerization to control Streptomyces development. Cell 158:1136–1147. https://doi.org/10.1016/j.cell.2014.07.022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. Vesper O, Amitai S, Belitsky M, Byrgazov K, Kaberdina AC, Engelberg-Kulka H, Moll I (2011) Selective translation of leaderless mRNAs by specialized ribosomes generated by MazF in Escherichia coli. Cell 147:147–157. https://doi.org/10.1016/j.cell.2011.07.047

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. Vockenhuber MP, Heueis N, Suess B (2015) Identification of metE as a second target of the sRNA scr5239 in Streptomyces coelicolor. PLoS ONE 10:e0120147. https://doi.org/10.1371/journal.pone.0120147

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. Vockenhuber MP, Suess B (2012) Streptomyces coelicolor sRNA scr5239 inhibits agarase expression by direct base pairing to the dagA coding region. Microbiology 158:424–435. https://doi.org/10.1099/mic.0.054205-0

    CAS  Article  PubMed  Google Scholar 

  95. Wakefield J, Hassan HM, Jaspars M, Ebel R, Rateb ME (2017) Dual induction of new microbial secondary metabolites by fungal bacterial co-cultivation. Front Microbiol 8:1284. https://doi.org/10.3389/fmicb.2017.01284

    Article  PubMed  PubMed Central  Google Scholar 

  96. Wang G, Hosaka T, Ochi K (2008) Dramatic activation of antibiotic production in Streptomyces coelicolor by cumulative drug resistance mutations. Appl Environ Microbiol 74:2834–2840. https://doi.org/10.1128/AEM.02800-07

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. Wang W, Li S, Li Z, Zhang J, Fan K, Tan G, Ai G, Lam SM, Shui G, Yang Z, Lu H, Jin P, Li Y, Chen X, Xia X, Liu X, Dannelly HK, Yang C, Yang Y, Zhang S, Alterovitz G, Xiang W, Zhang L (2020) Harnessing the intracellular triacylglycerols for titer improvement of polyketides in Streptomyces. Nat Biotechnol 38:76–83. https://doi.org/10.1038/s41587-019-0335-4

    CAS  Article  PubMed  Google Scholar 

  98. Wang Z, Gerstein M, Snyder M (2009) RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet 10:57–63. https://doi.org/10.1038/nrg2484

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. Wibberg D, Al-Dilaimi A, Busche T, Wedderhoff I, Schrempf H, Kalinowski J, de Orué O, Lucana D (2016) Complete genome sequence of Streptomyces reticuli, an efficient degrader of crystalline cellulose. J Biotechnol 222:13–14. https://doi.org/10.1016/j.jbiotec.2016.02.002

    CAS  Article  PubMed  Google Scholar 

  100. Wietzorrek A, Bibb M (1997) A novel family of proteins that regulates antibiotic production in streptomycetes appears to contain an OmpR-like DNA-binding fold. Mol Microbiol 25:1181–1184. https://doi.org/10.1046/j.1365-2958.1997.5421903.x

    CAS  Article  PubMed  Google Scholar 

  101. Wood DE, Lin H, Levy-Moonshine A, Swaminathan R, Chang YC, Anton BP, Osmani L, Steffen M, Kasif S, Salzberg SL (2012) Thousands of missed genes found in bacterial genomes and their analysis with COMBREX. Biol Direct 7:37. https://doi.org/10.1186/1745-6150-7-37

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  102. Woolstenhulme CJ, Guydosh NR, Green R, Buskirk AR (2015) High-precision analysis of translational pausing by ribosome profiling in bacteria lacking EFP. Cell Rep 11:13–21. https://doi.org/10.1016/j.celrep.2015.03.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Wu C, Du C, Gubbens J, Choi YH, van Wezel GP (2015) Metabolomics-driven discovery of a Prenylated isatin antibiotic produced by Streptomyces species MBT28. J Nat Prod 78:2355–2363. https://doi.org/10.1021/acs.jnatprod.5b00276

    CAS  Article  PubMed  Google Scholar 

  104. Yi JS, Kim MW, Kim M, Jeong Y, Kim EJ, Cho BK, Kim BG (2017) A novel approach for gene expression optimization through native promoter and 5' UTR combinations based on RNA-seq, Ribo-seq, and TSS-seq of Streptomyces coelicolor. ACS Synth Biol 6:555–565. https://doi.org/10.1021/acssynbio.6b00263

    CAS  Article  PubMed  Google Scholar 

  105. Zhang J, He Z, Xu J, Song S, Zhu Q, Wu G, Guan Y, Wu X, Yue R, Wang Y, Yu T, Hu S, Lu F, Zhang H (2020) Semi-rational mutagenesis of an industrial Streptomyces fungicidicus strain for improved enduracidin productivity. Appl Microbiol Biotechnol 104:3459–3471. https://doi.org/10.1007/s00253-020-10488-0

    CAS  Article  PubMed  Google Scholar 

  106. Zhang MM, Wong FT, Wang Y, Luo S, Lim YH, Heng E, Yeo WL, Cobb RE, Enghiad B, Ang EL, Zhao H (2017) CRISPR-Cas9 strategy for activation of silent Streptomyces biosynthetic gene clusters. Nat Chem Biol. https://doi.org/10.1038/nchembio.2341

    Article  PubMed  PubMed Central  Google Scholar 

  107. Zhao Y, Li L, Zheng G, Jiang W, Deng Z, Wang Z, Lu Y (2018) CRISPR/dCas9-mediated multiplex gene repression in Streptomyces. Biotechnol J 13:e1800121. https://doi.org/10.1002/biot.201800121

    CAS  Article  PubMed  Google Scholar 

  108. Zhu M, Mori M, Hwa T, Dai X (2019) Disruption of transcription-translation coordination in Escherichia coli leads to premature transcriptional termination. Nat Microbiol 4:2347–2356. https://doi.org/10.1038/s41564-019-0543-1

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by Bio & Medical Technology Development Program (2018M3A9F3079664 to B.-K.C.) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT). This work was also supported by a grant from the Novo Nordisk Foundation (NNF10CC1016517 to B.O.P).

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Lee, Y., Lee, N., Hwang, S. et al. System-level understanding of gene expression and regulation for engineering secondary metabolite production in Streptomyces. J Ind Microbiol Biotechnol 47, 739–752 (2020). https://doi.org/10.1007/s10295-020-02298-0

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Keywords

  • Streptomyces
  • Secondary metabolite
  • RNA
  • Transcription
  • Translation