Protein sequestration versus Hill‐type repression in circadian clock models

Abstract

Circadian (~24hr) clocks are self-sustained endogenous oscillators with which organisms keep track of daily and seasonal time. Circadian clocks frequently rely on interlocked transcriptionaltranslational feedback loops to generate rhythms that are robust against intrinsic and extrinsic perturbations. To investigate the dynamics and mechanisms of the intracellular feedback loops in circadian clocks, a number of mathematical models have been developed. The majority of the models use Hill functions to describe transcriptional repression in a way that is similar to the Goodwin model. Recently, a new class of models with protein sequestration-based repression has been introduced. Here, we discuss how this new class of models differs dramatically from those based on Hill-type repression in several fundamental aspects: conditions for rhythm generation, robust network designs and the periods of coupled oscillators. Consistently, these fundamental properties of circadian clocks also differ among Neurospora, Drosophila, and mammals depending on their key transcriptional repression mechanisms (Hill-type repression or protein sequestration). Based on both theoretical and experimental studies, this review highlights the importance of careful modeling of transcriptional repression mechanisms in molecular circadian clocks.

Stability of Wake-Sleep Cycles Requires Robust Degradation of the PERIOD Protein

“…On the other hand, varying V max leads to a larger change in period but a smaller change in amplitude and period stability than simulations with varying K d (Figure S7A). Similar patterns were also observed when different circadian clock models were used [54, 58, 59] (Figure S7B). …”

“…We have previously used the Kim-Forger circadian model, which describes the core transcriptional-translational negative feedback loop of the circadian clock [14, 54], but uses a simple linear degradation process for PER. Recent studies have shown that a Michaelis-Menten type of degradation can be used to simulate the biological proteasomal degradation involving multiple components such as ubiquitin; E1, E2, and E3 enzymes; deubiquitinases; and the proteasome [55, 56].…”

“…The modified Kim-Forger model [14] [59] [54], where repressor (R) nonlinearly degrades, is described with the following equation:…”

Model-driven experimental approach reveals the complex regulatory distribution of p53 by the circadian factor Period 2

“…Endogenous protein levels were determined by immunoblotting and quantitated using the ImageJ software, version 1.45 [NIH software package (40)] or Image Lab Software followed by detection using Gel Doc XR+ System (Bio-Rad). For mathematical modeling, we extended a previous model of the intracellular mammalian circadian clock (24,25) to describe interactions between p53 and Per2 ( Fig. 2 A and D).…”

“…2D, Tables S2 and S3, and SI Materials and Methods). First, we modified the Kim and Forger's model used to represent the dynamics of the transcriptional negative arm generated by Per2 (24,25). Second, we considered the ubiquitination status of p53 as it modulates p53 degradation and shuttling (26).…”