Eukaryotic gene regulation at equilibrium, or non?

Zoller, Benjamin; Gregor, Thomas; Tkačik, Gašper

doi:10.1016/j.coisb.2022.100435

Cited by 15 publications

(14 citation statements)

References 84 publications

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“…As more and more quantitative measurements will become available and the ability to capture interdependencies between regulatory factors increases, we expect that the complexity of the system will increasingly demand mathematical and physical modeling to provide a thorough and quantitative understanding of the regulatory processes [ 5 , 115 ]. In addition, the presence of energy expending mechanisms in transcription demands new kinetic models to investigate the nonequilibrium nature of eukaryotic gene regulation [ 67 , 71 , 72 , 120 ]. Last, the ability to specifically edit mammalian genomes has substantially increased in recent years, allowing for more mechanistic studies, but it nevertheless remains essential to continue to use diverse model organisms to exploit the natural variation in nuclear environments, 3D genome architecture, and regulatory complexity to reveal the scope of possible regulatory mechanisms at different scales.…”

Section: Discussionmentioning

confidence: 99%

Time will tell: comparing timescales to gain insight into transcriptional bursting

Meeussen,

Lenstra

2024

Trends in Genetics

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Section: Discussionmentioning

confidence: 99%

Time will tell: comparing timescales to gain insight into transcriptional bursting

Meeussen,

Lenstra

2024

Trends in Genetics

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“…The common definition of the protein half-life or protein turnover characteristic time τ PT relies on the hypothesis that s and k are constants, that is, time-independent (Figure 1A), and that a steady-state can be reached. This assumption is unsustainable in most biologically relevant conditions, 14,83 since protein synthesis and decay rates often vary over time, for example, during the cell cycle 78 or after cell stimulation. 15 Therefore, protein levels at equilibrium P eq ; and thus, the characteristic time of protein turnover τ PT cannot be defined.…”

Section: Beyond the Equilibrium Definition Of Protein Turnover: Turno...mentioning

confidence: 99%

“…Finding an operative definition of PT in this regime remains thus an open challenge. 14 In this Hypothesis, after a short review of previous work in the field (1) We discuss a new formalism to quantify protein turnover in both equilibrium and out-of-equilibrium contexts; (2) We show how it can be applied to existing data measuring proteome dynamics, and that this new conceptual framework highlights that bone-marrow-derived mouse dendritic cells exhibit proteome-wide protein turnover changes upon LPS stimulation. 15…”

Section: Introductionmentioning

confidence: 99%

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An out‐of‐equilibrium definition of protein turnover

Martin

Suter

2023

BioEssays

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Protein turnover (PT) has been formally defined only in equilibrium conditions, which is ill‐suited to quantify PT during dynamic processes that occur during embryogenesis or (extra) cellular signaling. In this Hypothesis, we propose a definition of PT in an out‐of‐equilibrium regime that allows the quantification of PT in virtually any biological context. We propose a simple mathematical and conceptual framework applicable to a broad range of available data, such as RNA sequencing coupled with pulsed‐SILAC datasets. We apply our framework to a published dataset and show that stimulation of mouse dendritic cells with LPS leads to a proteome‐wide change in PT. This is the first quantification of PT out‐of‐equilibrium, paving the way for the analysis of biological systems in other contexts.

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“…But many challenges at the frontier of molecular biology today unavoidably require tackling nonequilibrium. For example, many aspects of gene regulation in eukaryotes [13][14][15] -from the spreading of epigenetic marks 16 to the action of enhancers 17,18 -have inspired the use of nonequilibrium models. These models confront us with many parameters we cannot measure or handle analytically.…”

mentioning

confidence: 99%

Size limits the sensitivity of kinetic schemes

Owen

Horowitz

2023

Nat Commun

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Living things benefit from exquisite molecular sensitivity in many of their key processes, including DNA replication, transcription and translation, chemical sensing, and morphogenesis. At thermodynamic equilibrium, the basic biophysical mechanism for sensitivity is cooperative binding, for which it can be shown that the Hill coefficient, a sensitivity measure, cannot exceed the number of binding sites. Generalizing this fact, we find that for any kinetic scheme, at or away from thermodynamic equilibrium, a very simple structural quantity, the size of the support of a perturbation, always limits the effective Hill coefficient. We show how this bound sheds light on and unifies diverse sensitivity mechanisms, including kinetic proofreading and a nonequilibrium Monod-Wyman-Changeux (MWC) model proposed for the E. coli flagellar motor switch, representing in each case a simple, precise bridge between experimental observations and the models we write down. In pursuit of mechanisms that saturate the support bound, we find a nonequilibrium binding mechanism, nested hysteresis, with sensitivity exponential in the number of binding sites, with implications for our understanding of models of gene regulation and the function of biomolecular condensates.

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Eukaryotic gene regulation at equilibrium, or non?

Cited by 15 publications

References 84 publications

Time will tell: comparing timescales to gain insight into transcriptional bursting

Time will tell: comparing timescales to gain insight into transcriptional bursting

An out‐of‐equilibrium definition of protein turnover

Size limits the sensitivity of kinetic schemes

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