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1. Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria

Author

Mu, A, Klare, WP, Baines, SL, Ignatius Pang, CN, Guérillot, R, Harbison-Price, N, Keller, N, Wilksch, J, Nhu, NTK, Phan, MD, Keller, B, Nijagal, B, Tull, D, Dayalan, S, Chua, HHC, Skoneczny, D, Koval, J ; https://orcid.org/0000-0003-4270-0534, Hachani, A, Shah, AD, Neha, N, Jadhav, S, Partridge, SR, Cork, AJ, Peters, K, Bertolla, O, Brouwer, S, Hancock, SJ, Álvarez-Fraga, L, De Oliveira, DMP, Forde, B, Dale, A, Mujchariyakul, W, Walsh, CJ, Monk, I, Fitzgerald, A, Lum, M, Correa-Ospina, C, Roy Chowdhury, P, Parton, RG, De Voss, J, Beckett, J, Monty, F, McKinnon, J, Song, X, Stephen, JR, Everest, M, Bellgard, MI, Tinning, M, Leeming, M, Hocking, D, Jebeli, L, Wang, N, Ben Zakour, N, Yasar, SA ; https://orcid.org/0000-0002-3176-8376, Vecchiarelli, S, Russell, T, Zaw, T, Chen, T, Teng, D, Kassir, Z, Lithgow, T, Jenney, A, Cole, JN, Nizet, V, Sorrell, TC, Peleg, AY, Paterson, DL, Beatson, SA, Wu, J, Molloy, MP, Syme, AE, Goode, RJA, Hunter, AA, Bowland, G, West, NP, Wilkins, MR ; https://orcid.org/0000-0002-5700-5684, Djordjevic, SP, Davies, MR, Seemann, T, Howden, BP, Pascovici, D, Tyagi, S, Schittenhelm, RB, De Souza, DP, McConville, MJ, Iredell, JR, Cordwell, SJ, Strugnell, RA, Stinear, TP, Schembri, MA, Walker, MJ, Pang, Ignatius ; https://orcid.org/0000-0001-9703-5741, Mu, A, Klare, WP, Baines, SL, Ignatius Pang, CN, Guérillot, R, Harbison-Price, N, Keller, N, Wilksch, J, Nhu, NTK, Phan, MD, Keller, B, Nijagal, B, Tull, D, Dayalan, S, Chua, HHC, Skoneczny, D, Koval, J ; https://orcid.org/0000-0003-4270-0534, Hachani, A, Shah, AD, Neha, N, Jadhav, S, Partridge, SR, Cork, AJ, Peters, K, Bertolla, O, Brouwer, S, Hancock, SJ, Álvarez-Fraga, L, De Oliveira, DMP, Forde, B, Dale, A, Mujchariyakul, W, Walsh, CJ, Monk, I, Fitzgerald, A, Lum, M, Correa-Ospina, C, Roy Chowdhury, P, Parton, RG, De Voss, J, Beckett, J, Monty, F, McKinnon, J, Song, X, Stephen, JR, Everest, M, Bellgard, MI, Tinning, M, Leeming, M, Hocking, D, Jebeli, L, Wang, N, Ben Zakour, N, Yasar, SA ; https://orcid.org/0000-0002-3176-8376, Vecchiarelli, S, Russell, T, Zaw, T, Chen, T, Teng, D, Kassir, Z, Lithgow, T, Jenney, A, Cole, JN, Nizet, V, Sorrell, TC, Peleg, AY, Paterson, DL, Beatson, SA, Wu, J, Molloy, MP, Syme, AE, Goode, RJA, Hunter, AA, Bowland, G, West, NP, Wilkins, MR ; https://orcid.org/0000-0002-5700-5684, Djordjevic, SP, Davies, MR, Seemann, T, Howden, BP, Pascovici, D, Tyagi, S, Schittenhelm, RB, De Souza, DP, McConville, MJ, Iredell, JR, Cordwell, SJ, Strugnell, RA, Stinear, TP, Schembri, MA, Walker, MJ, and Pang, Ignatius ; https://orcid.org/0000-0001-9703-5741

Abstract

Even in the setting of optimal resuscitation in high-income countries severe sepsis and septic shock have a mortality of 20–40%, with antibiotic resistance dramatically increasing this mortality risk. To develop a reference dataset enabling the identification of common bacterial targets for therapeutic intervention, we applied a standardized genomic, transcriptomic, proteomic and metabolomic technological framework to multiple clinical isolates of four sepsis-causing pathogens: Escherichia coli, Klebsiella pneumoniae species complex, Staphylococcus aureus and Streptococcus pyogenes. Exposure to human serum generated a sepsis molecular signature containing global increases in fatty acid and lipid biosynthesis and metabolism, consistent with cell envelope remodelling and nutrient adaptation for osmoprotection. In addition, acquisition of cholesterol was identified across the bacterial species. This detailed reference dataset has been established as an open resource to support discovery and translational research.

Published
2023

2. Knockout of the Hmt1p arginine methyltransferase in saccharomyces cerevisiae leads to the dysregulation of phosphate-associated genes and processes

Author

Chia, SZ, Lai, YW, Yagoub, D, Lev, S, Hamey, JJ ; https://orcid.org/0000-0002-0463-8955, Ignatius Pang, CN, Desmarini, D, Chen, Z, Djordjevic, JT, Erce, MA, Hart-Smith, G ; https://orcid.org/0000-0003-3907-0367, Wilkins, MR ; https://orcid.org/0000-0002-5700-5684, Pang, Ignatius ; https://orcid.org/0000-0001-9703-5741, Chia, SZ, Lai, YW, Yagoub, D, Lev, S, Hamey, JJ ; https://orcid.org/0000-0002-0463-8955, Ignatius Pang, CN, Desmarini, D, Chen, Z, Djordjevic, JT, Erce, MA, Hart-Smith, G ; https://orcid.org/0000-0003-3907-0367, Wilkins, MR ; https://orcid.org/0000-0002-5700-5684, and Pang, Ignatius ; https://orcid.org/0000-0001-9703-5741

Abstract

Hmt1p is the predominant arginine methyltransferase in Saccharomyces cerevisiae. Its substrate proteins are involved in transcription, transcriptional regulation, nucleocytoplasmic transport and RNA splicing. Hmt1p-catalyzed methylation can also modulate protein-protein interactions. Hmt1p is conserved from unicellular eukaryotes through to mammals where its ortholog, PRMT1, is lethal upon knockout. In yeast, however, the effect of knockout on the transcriptome and proteome has not been described. Transcriptome analysis revealed downregulation of phosphate-responsive genes in hmt1, including acid phosphatases PHO5, PHO11, and PHO12, phosphate transporters PHO84 and PHO89 and the vacuolar transporter chaperone VTC3. Analysis of the hmt1 proteome revealed decreased abundance of phosphate-associated proteins including phosphate transporter Pho84p, vacuolar alkaline phosphatase Pho8p, acid phosphatase Pho3p and subunits of the vacuolar transporter chaperone complex Vtc1p, Vtc3p and Vtc4p. Consistent with this, phosphate homeostasis was dysregulated in hmt1 cells, showing decreased extracellular phosphatase levels and decreased total Pi in phosphate-depleted medium. In vitro, we showed that transcription factor Pho4p can be methylated at Arg-241, which could explain phosphate dysregulation in hmt1 if interplay exists with phosphorylation at Ser-242 or Ser-243, or if Arg-241 methylation affects the capacity of Pho4p to homodimerize or interact with Pho2p. However, the Arg-241 methylation site was not validated in vivo and the localization of a Pho4p-GFP fusion in hmt1 was not different from wild type. To our knowledge, this is the first study to reveal an association between Hmt1p and phosphate homeostasis and one which suggests a regulatory link between S-adenosyl methionine and intracellular phosphate.

Published
2018

3. Integrative omics identifies conserved and pathogen-specific responses of sepsis-causing bacteria.

Author

Mu A, Klare WP, Baines SL, Ignatius Pang CN, Guérillot R, Harbison-Price N, Keller N, Wilksch J, Nhu NTK, Phan MD, Keller B, Nijagal B, Tull D, Dayalan S, Chua HHC, Skoneczny D, Koval J, Hachani A, Shah AD, Neha N, Jadhav S, Partridge SR, Cork AJ, Peters K, Bertolla O, Brouwer S, Hancock SJ, Álvarez-Fraga L, De Oliveira DMP, Forde B, Dale A, Mujchariyakul W, Walsh CJ, Monk I, Fitzgerald A, Lum M, Correa-Ospina C, Roy Chowdhury P, Parton RG, De Voss J, Beckett J, Monty F, McKinnon J, Song X, Stephen JR, Everest M, Bellgard MI, Tinning M, Leeming M, Hocking D, Jebeli L, Wang N, Ben Zakour N, Yasar SA, Vecchiarelli S, Russell T, Zaw T, Chen T, Teng D, Kassir Z, Lithgow T, Jenney A, Cole JN, Nizet V, Sorrell TC, Peleg AY, Paterson DL, Beatson SA, Wu J, Molloy MP, Syme AE, Goode RJA, Hunter AA, Bowland G, West NP, Wilkins MR, Djordjevic SP, Davies MR, Seemann T, Howden BP, Pascovici D, Tyagi S, Schittenhelm RB, De Souza DP, McConville MJ, Iredell JR, Cordwell SJ, Strugnell RA, Stinear TP, Schembri MA, and Walker MJ

Subjects
Humans, Anti-Bacterial Agents therapeutic use, Proteomics, Bacteria, Escherichia coli, Klebsiella, Microbial Sensitivity Tests, Sepsis microbiology, Staphylococcal Infections
Abstract

Even in the setting of optimal resuscitation in high-income countries severe sepsis and septic shock have a mortality of 20-40%, with antibiotic resistance dramatically increasing this mortality risk. To develop a reference dataset enabling the identification of common bacterial targets for therapeutic intervention, we applied a standardized genomic, transcriptomic, proteomic and metabolomic technological framework to multiple clinical isolates of four sepsis-causing pathogens: Escherichia coli, Klebsiella pneumoniae species complex, Staphylococcus aureus and Streptococcus pyogenes. Exposure to human serum generated a sepsis molecular signature containing global increases in fatty acid and lipid biosynthesis and metabolism, consistent with cell envelope remodelling and nutrient adaptation for osmoprotection. In addition, acquisition of cholesterol was identified across the bacterial species. This detailed reference dataset has been established as an open resource to support discovery and translational research., (© 2023. The Author(s).)

Published
2023
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4. Investigating the Network Basis of Negative Genetic Interactions in Saccharomyces cerevisiae with Integrated Biological Networks and Triplet Motif Analysis.

Author

Ignatius Pang CN, Goel A, and Wilkins MR

Subjects
Amino Acid Sequence, Computational Biology, Gene Regulatory Networks, Protein Interaction Mapping, Protein Kinases genetics, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae Proteins classification, Saccharomyces cerevisiae Proteins genetics, Signal Transduction, Transcription Factors genetics, Gene Expression Regulation, Fungal, Protein Kinases metabolism, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins metabolism, Transcription Factors metabolism
Abstract

Negative genetic interactions in Saccharomyces cerevisiae have been systematically screened to near-completeness, with >500 000 interactions identified. Nevertheless, the biological basis of these interactions remains poorly understood. To investigate this, we analyzed negative genetic interactions within an integrated biological network, being the union of protein-protein, kinase-substrate, and transcription factor-target gene interactions. Network triplets, containing two genes/proteins that show negative genetic interaction and a third protein from the network, were then analyzed. Strikingly, just six out of 15 possible triplet motif types were present, as compared to randomized networks. These were in three clear groups: protein-protein interactions, signaling, and regulatory triplets where the latter two showed no overlap. In the triplets, negative genetic interactions were associated with paralogs and ohnologs; however, these were very rare. Negative genetic interactions among the six triplet motifs did however show strong dosage constraints, with genes being significantly associated with toxicity on overexpression and periodicity in the cell cycle. Negative genetic interactions overlapped with other interaction types in 37% of cases; these were predominantly associated with protein complexes or signaling events. Finally, we highlight regions of "network vulnerability" containing multiple negative genetic interactions; these could be targeted in fungal species for the regulation of cell growth.

Published
2018
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