The interplay between metabolic stochasticity and cAMP-CRP regulation in single E. coli cells

Martijn Wehrens; Laurens H J Krah; Benjamin D Towbin; Rutger Hermsen; Sander J Tans

doi:10.1016/j.celrep.2023.113284

The interplay between metabolic stochasticity and cAMP-CRP regulation in single E. coli cells

Martijn Wehrens
, Laurens H J Krah
, Benjamin D Towbin
, Rutger Hermsen
, Sander J Tans^*

^*Corresponding author for this work

Hubrecht Institute
University of Bern
Delft University of Technology

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The inherent stochasticity of metabolism raises a critical question for understanding homeostasis: are cellular processes regulated in response to internal fluctuations? Here, we show that, in E. coli cells under constant external conditions, catabolic enzyme expression continuously responds to metabolic fluctuations. The underlying regulatory feedback is enabled by the cyclic AMP (cAMP) and cAMP receptor protein (CRP) system, which controls catabolic enzyme expression based on metabolite concentrations. Using single-cell microscopy, genetic constructs in which this feedback is disabled, and mathematical modeling, we show how fluctuations circulate through the metabolic and genetic network at sub-cell-cycle timescales. Modeling identifies four noise propagation modes, including one specific to CRP regulation. Together, these modes correctly predict noise circulation at perturbed cAMP levels. The cAMP-CRP system may thus have evolved to control internal metabolic fluctuations in addition to external growth conditions. We conjecture that second messengers may more broadly function to achieve cellular homeostasis.

Original language	English
Article number	113284
Number of pages	17
Journal	Cell Reports
Volume	42
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2023.113284
Publication status	Published - 31 Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Funding

L.H.J.K. was supported by the Dutch Research Council ( NWO , www.nwo.nl ; grant 022.005.023 ). This work received funding from the Swiss National Science Foundation (SNSF) in the form of an Eccellenza Professorial Fellowship ( PCEFP3_181204 ) to B.D.T. Work in the group of S.J.T. is supported by the Dutch Research Council (NWO).

Funders	Funder number
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	PCEFP3_181204
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	022.005.023

Keywords

CP: Cell biology
CP: Microbiology
CRP
Escherichia coli
cAMP-CRP
gene expression
heterogeneity
noise
regulation
single cell
stochasticity
time lapse microscopy

Access to Document

10.1016/j.celrep.2023.113284Licence: CC BY

PIIS2211124723012962Final published version, 3.96 MBLicence: CC BY

Cite this

@article{01d6860c5112456dab9c2ec742e1f620,

title = "The interplay between metabolic stochasticity and cAMP-CRP regulation in single E. coli cells",

abstract = "The inherent stochasticity of metabolism raises a critical question for understanding homeostasis: are cellular processes regulated in response to internal fluctuations? Here, we show that, in E. coli cells under constant external conditions, catabolic enzyme expression continuously responds to metabolic fluctuations. The underlying regulatory feedback is enabled by the cyclic AMP (cAMP) and cAMP receptor protein (CRP) system, which controls catabolic enzyme expression based on metabolite concentrations. Using single-cell microscopy, genetic constructs in which this feedback is disabled, and mathematical modeling, we show how fluctuations circulate through the metabolic and genetic network at sub-cell-cycle timescales. Modeling identifies four noise propagation modes, including one specific to CRP regulation. Together, these modes correctly predict noise circulation at perturbed cAMP levels. The cAMP-CRP system may thus have evolved to control internal metabolic fluctuations in addition to external growth conditions. We conjecture that second messengers may more broadly function to achieve cellular homeostasis.",

keywords = "CP: Cell biology, CP: Microbiology, CRP, Escherichia coli, cAMP-CRP, gene expression, heterogeneity, noise, regulation, single cell, stochasticity, time lapse microscopy",

author = "Martijn Wehrens and Krah, \{Laurens H J\} and Towbin, \{Benjamin D\} and Rutger Hermsen and Tans, \{Sander J\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = oct,

day = "31",

doi = "10.1016/j.celrep.2023.113284",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier BV",

number = "10",

}

TY - JOUR

T1 - The interplay between metabolic stochasticity and cAMP-CRP regulation in single E. coli cells

AU - Wehrens, Martijn

AU - Krah, Laurens H J

AU - Towbin, Benjamin D

AU - Hermsen, Rutger

AU - Tans, Sander J

PY - 2023/10/31

Y1 - 2023/10/31

N2 - The inherent stochasticity of metabolism raises a critical question for understanding homeostasis: are cellular processes regulated in response to internal fluctuations? Here, we show that, in E. coli cells under constant external conditions, catabolic enzyme expression continuously responds to metabolic fluctuations. The underlying regulatory feedback is enabled by the cyclic AMP (cAMP) and cAMP receptor protein (CRP) system, which controls catabolic enzyme expression based on metabolite concentrations. Using single-cell microscopy, genetic constructs in which this feedback is disabled, and mathematical modeling, we show how fluctuations circulate through the metabolic and genetic network at sub-cell-cycle timescales. Modeling identifies four noise propagation modes, including one specific to CRP regulation. Together, these modes correctly predict noise circulation at perturbed cAMP levels. The cAMP-CRP system may thus have evolved to control internal metabolic fluctuations in addition to external growth conditions. We conjecture that second messengers may more broadly function to achieve cellular homeostasis.

AB - The inherent stochasticity of metabolism raises a critical question for understanding homeostasis: are cellular processes regulated in response to internal fluctuations? Here, we show that, in E. coli cells under constant external conditions, catabolic enzyme expression continuously responds to metabolic fluctuations. The underlying regulatory feedback is enabled by the cyclic AMP (cAMP) and cAMP receptor protein (CRP) system, which controls catabolic enzyme expression based on metabolite concentrations. Using single-cell microscopy, genetic constructs in which this feedback is disabled, and mathematical modeling, we show how fluctuations circulate through the metabolic and genetic network at sub-cell-cycle timescales. Modeling identifies four noise propagation modes, including one specific to CRP regulation. Together, these modes correctly predict noise circulation at perturbed cAMP levels. The cAMP-CRP system may thus have evolved to control internal metabolic fluctuations in addition to external growth conditions. We conjecture that second messengers may more broadly function to achieve cellular homeostasis.

KW - CP: Cell biology

KW - CP: Microbiology

KW - CRP

KW - Escherichia coli

KW - cAMP-CRP

KW - gene expression

KW - heterogeneity

KW - noise

KW - regulation

KW - single cell

KW - stochasticity

KW - time lapse microscopy

UR - https://www.scopus.com/pages/publications/85174463577

U2 - 10.1016/j.celrep.2023.113284

DO - 10.1016/j.celrep.2023.113284

M3 - Article

C2 - 37864793

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 10

M1 - 113284

ER -

The interplay between metabolic stochasticity and cAMP-CRP regulation in single E. coli cells

Abstract

Bibliographical note

Funding

Keywords

Access to Document

Other files and links

Fingerprint

Cite this