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Synchronisation und Entrainment circadianer Systeme: Oszillatortheorie trifft Chronobiologie

Antragsteller Dr. Christoph Schmal
Fachliche Zuordnung Bioinformatik und Theoretische Biologie
Förderung Förderung von 2018 bis 2023
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 414704559
 
Erstellungsjahr 2023

Zusammenfassung der Projektergebnisse

Circadian clocks are heritable endogenous pacemakers that integrate different scales of spatiotemporal organization. Intra-cellular delayed negative feedback loops generate circadian rhythmicity in single cells which further coordinate at the tissue level through mutual interactions. Emergent properties that arise through these interactions impact the entrainment to external Zeitgeber signals. The goal of this interdisciplinary project was to develop a better understanding how single cellular but also emergent properties that arise at the tissue level affect the generation of circadian rhythms and subsequently its entrainment characteristics. We are able to report advances at the different layers of this hierarchical organization. Using biophysically inspired detailed molecular models of the circadian clock we were able to reveal fundamental design principles underlying the intrinsic circadian rhythm generation. We report that the topology of the intracellular gene regulatory network that is based on multiple interlocked transcriptional-translational negative feedback loops can lead to the emergence of several non-linear phenomena such as splitting, period doubling and even deterministic chaos. We could show that a relatively weak coupling between the different sub-loops of this intracellular network explains a previously not-well understood phenomenon, namely the transient dynamical dissociation of different clock genes after external perturbations such as light pulses or jet-lag. On top of that we could show that the impact of the various clock genes varies at different developmental stages. In a bioinformatic study that combines a large scale RNAi screen with 3’-end-RNAseq and mass-spectrometry based proteomics we further advanced our understanding of a fundamental property of circadian rhythms, namely the relative resilience of circadian free-running periods with respect to temperature known as temperature compensation. We revealed that polyadenylation factor CPSF6 regulates temperature compensation of the circadian clock. In a series of manuscripts, we further advanced our understanding of circadian entrainment. We could show that relatively simple systems consisting of a single circadian oscillator subject to an external Zeitgeber cycle are able explain a large variety of complex non-linear entrainment data. Using a global parameter search and/or global optimization we could show that conceptual amplitude-phase models as well as the Goodwin oscillator, a minimal molecular model of the circadian clock, are able to reproduce known features of vertebrate clocks such as small amplitude PRCs, short jet-lag durations and seasonal phase variability. Using a data-driven modeling approach, we reveal design principles underlying the complex dynamical phenomena underlying circadian temperature entrainment of the red bread mold Neurospora crassa. Finally, we investigated the entrainment of circadian system under ecologically relevant conditions of realistic natural light conditions. By this, we reveal the dependence of important entrainment characteristics such as entrainment ranges or the distribution of chronotypes on season or geographical latitude.

Projektbezogene Publikationen (Auswahl)

 
 

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