Proteome allocation is linked to transcriptional regulation through a modularized transcriptome

Patel, Arjun; McGrosso, Dominic; Hefner, Ying; Campeau, Anaamika; Sastry, Anand V.; Maurya, Svetlana Rajkumar; Rychel, Kevin; Gonzalez, David J.; Palsson, Bernhard Ø.

doi:10.1101/2023.02.20.529291

Cited by 4 publications

(5 citation statements)

References 55 publications

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“…The transcriptomic re-allocation involves a consistent set of iModulons with known functions. The relationship between the proteome and transcriptome functions enable genome-scale computational biology assessment of the phenotypic consequences of the reallocation 49 . Thus, a detailed understanding of the effects of the f/g tradeoff at the systems level has emerged.…”

Section: Discussionmentioning

confidence: 99%

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The hallmarks of a tradeoff in transcriptomes that balances stress and growth functions

Dalldorf

Rychel

Szubin

et al. 2023

Preprint

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Fit phenotypes are achieved through optimal transcriptomic allocation. Here, we performed a high-resolution, multi-scale study of the transcriptomic tradeoff between two key fitness phenotypes, stress response (fear) and growth (greed), in Escherichia coli. We introduced twelve RNA polymerase (RNAP) mutations commonly acquired during adaptive laboratory evolution (ALE) and found that single mutations resulted in large shifts in the fear vs. greed tradeoff, likely through destabilizing the rpoB-rpoC interface. RpoS and GAD regulons drive the fear response while ribosomal proteins and the ppGpp regulon underlie greed. Growth rate selection pressure during ALE results in endpoint strains that often have RNAP mutations, with synergistic mutations reflective of particular conditions. A phylogenetic analysis found the tradeoff in numerous bacteria species. The results suggest that the fear vs. greed tradeoff represents a general principle of transcriptome allocation in bacteria where small genetic changes can result in large phenotypic adaptations to growth conditions.

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Section: Discussionmentioning

confidence: 99%

“…This value is calculated for every sample and plotted against its corresponding PRECISE iModulon Activity. The proteomic calculations performed for this paper are well described in Patel et al 49 .…”

Section: Metabolic Model and Proteomic Calculationsmentioning

confidence: 99%

The hallmarks of a tradeoff in transcriptomes that balances stress and growth functions

Dalldorf

Rychel

Szubin

et al. 2023

Preprint

Self Cite

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“…As additional versions of PRECISE are created using more data, it is likely additional iModulons could be included in this tradeoff. The relationship between the proteome and transcriptome functions enables genome-scale computational biology assessment of the phenotypic consequences of the reallocation ( 57 ). Thus, a detailed understanding of the effects of the f/g tradeoff at the systems level has emerged.…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The hallmarks of a tradeoff in transcriptomes that balances stress and growth functions

Dalldorf,

Rychel,

Szubin

et al. 2024

mSystems

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Fast growth phenotypes are achieved through optimal transcriptomic allocation, in which cells must balance tradeoffs in resource allocation between diverse functions. One such balance between stress readiness and unbridled growth in E. coli has been termed the fear versus greed (f/g) tradeoff. Two specific RNA polymerase (RNAP) mutations observed in adaptation to fast growth have been previously shown to affect the f/g tradeoff, suggesting that genetic adaptations may be primed to control f/g resource allocation. Here, we conduct a greatly expanded study of the genetic control of the f/g tradeoff across diverse conditions. We introduced 12 RNA polymerase (RNAP) mutations commonly acquired during adaptive laboratory evolution (ALE) and obtained expression profiles of each. We found that these single RNAP mutation strains resulted in large shifts in the f/g tradeoff primarily in the RpoS regulon and ribosomal genes, likely through modifying RNAP-DNA interactions. Two of these mutations additionally caused condition-specific transcriptional adaptations. While this tradeoff was previously characterized by the RpoS regulon and ribosomal expression, we find that the GAD regulon plays an important role in stress readiness and ppGpp in translation activity, expanding the scope of the tradeoff. A phylogenetic analysis found the greed-related genes of the tradeoff present in numerous bacterial species. The results suggest that the f/g tradeoff represents a general principle of transcriptome allocation in bacteria where small genetic changes can result in large phenotypic adaptations to growth conditions. IMPORTANCE To increase growth, E. coli must raise ribosomal content at the expense of non-growth functions. Previous studies have linked RNAP mutations to this transcriptional shift and increased growth but were focused on only two mutations found in the protein’s central region. RNAP mutations, however, commonly occur over a large structural range. To explore RNAP mutations’ impact, we have introduced 12 RNAP mutations found in laboratory evolution experiments and obtained expression profiles of each. The mutations nearly universally increased growth rates by adjusting said tradeoff away from non-growth functions. In addition to this shift, a few caused condition-specific adaptations. We explored the prevalence of this tradeoff across phylogeny and found it to be a widespread and conserved trend among bacteria.

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“…We generated three strains for analysis: 1) wild type, identical to the base iJL1678b model; 2) FermNull, as described above; and 3) FermNull + nfsB, as described above. We estimated the NfsB k eff value to be 57.4 in the model using the transcriptome-constrained wild-type flux state and experimental absolute proteomics from this study 136 . All strains were grown anaerobically, with growth being the primary objective for simulations.…”

Section: Modeling Of Hnq-mediated Eetmentioning

confidence: 99%

Extracellular Respiration is a Latent Energy Metabolism inEscherichia coli

Kundu,

Krishnan,

Szubin

et al. 2024

Preprint

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Diverse microbial species utilize redox shuttles to exchange electrons with their environment through mediated extracellular electron transfer (EET). This process maintains redox homeostasis and supports anaerobic survival across diverse microbial communities. Although mediated EET has been extensively leveraged for bioelectrocatalysis and bioelectronics for decades, fundamental questions remain about how these redox shuttles are reduced within cells and their bioenergetic implications. This knowledge gap limits our understanding of the physiological roles of mediated EET in various microbes and hampers the development of efficient microbial electrochemical technologies. To address this, we developed a methodology integrating genome editing, electrochemistry, and systems biology to investigate the mechanism and bioenergetic implications of mediated EET in bacteria. Using this approach, we uncovered a mediated EET mechanism inEscherichia coli. In the absence of alternative electron sinks, the redox cycling of 2-hydroxy-1,4-naphthoquinone (HNQ) via a cytoplasmic nitroreductase enabledE. colito respire and grow on an extracellular electrode. Genome-scale metabolic modeling suggested that HNQ- mediated EET offers a more energetically favorable route for supporting anaerobic growth than canonical fermentation. Transcriptome analysis revealed redox perturbations in response to HNQ and identified rapid metabolic adaptations that support growth. This work demonstrates thatE. colican grow independently of classical electron transport chains and fermentative pathways, unveiling a new type of anaerobic energy metabolism.

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Proteome allocation is linked to transcriptional regulation through a modularized transcriptome

Cited by 4 publications

References 55 publications

The hallmarks of a tradeoff in transcriptomes that balances stress and growth functions

The hallmarks of a tradeoff in transcriptomes that balances stress and growth functions

The hallmarks of a tradeoff in transcriptomes that balances stress and growth functions

Extracellular Respiration is a Latent Energy Metabolism inEscherichia coli

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