Universität zu Köln

Bhogale, Prasanna M., Sorg, Robin A., Veening, Jan-Willem ORCID: 0000-0002-3162-6634 and Berg, Johannes ORCID: 0000-0001-6569-3061 (2022). Switching off: The phenotypic transition to the uninduced state of the lactose uptake pathway. Biophys. J., 121 (2). S. 183 - 193. CAMBRIDGE: CELL PRESS. ISSN 1542-0086

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Abstract

The lactose uptake pathway of E. coli is a paradigmatic example of multistability in gene regulatory circuits. In the induced state of the lac pathway, the genes comprising the lac operon are transcribed, leading to the production of proteins that import and metabolize lactose. In the uninduced state, a stable repressor-DNA loop frequently blocks the transcription of the lac genes. Transitions from one phenotypic state to the other are driven by fluctuations, which arise from the random timing of the binding of ligands and proteins. This stochasticity affects transcription and translation, and ultimately molecular copy numbers. Our aim is to understand the transition from the induced to the uninduced state of the lac operon. We use a detailed computa-tional model to show that repressor-operator binding and unbinding, fluctuations in the total number of repressors, and inducer-repressor binding and unbinding all play a role in this transition. Based on the timescales on which these processes operate, we construct a minimal model of the transition to the uninduced state and compare the results with simulations and experimental observations. The induced state turns out to be very stable, with a transition rate to the uninduced state lower than 2x 10-9 per minute. In contrast to the transition to the induced state, the transition to the uninduced state is well described in terms of a 2D diffusive system crossing a barrier, with the diffusion rates emerging from a model of repressor unbinding. SIGNIFICANCE Gene regulatory circuits can encode different phenotypic states by stabilizing feedback: once a circuit is activated, this state can persist for a long time, and vice versa. However, transitions between different phenotypic states occur as the result of unavoidable stochastic noise in gene expression or in ligand binding. We look at a paradigmatic gene regulatory circuit, the lactose uptake pathway, and determine which types of fluctuations drive the transition from the induced to the uninduced state. The methods we develop here allow to systematically reduce the complexity of a circuit while retaining the rate-limiting fluctuations and hence to build simple effective models of complex circuits.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bhogale, Prasanna M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sorg, Robin A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Veening, Jan-Willem UNSPECIFIED orcid.org/0000-0002-3162-6634 UNSPECIFIED Berg, Johannes UNSPECIFIED orcid.org/0000-0001-6569-3061 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-673658
DOI:	10.1016/j.bpj.2021.12.027
Journal or Publication Title:	Biophys. J.
Volume:	121
Number:	2
Page Range:	S. 183 - 193
Date:	2022
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1542-0086
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENE-EXPRESSION; LAC OPERON; CELL FATE; DYNAMICS; NOISE; BISTABILITY; DETERMINES; INDUCTION; BINDING Multiple languages Biophysics Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67365