Hanspeter Herzel

Hanspeter Herzel
Humboldt-Universität zu Berlin | HU Berlin · Institute for Theoretical Biology (ITB)

Prof.

About

446
Publications
59,125
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14,849
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Additional affiliations
October 1996 - present
Charité Universitätsmedizin Berlin
Position
  • Researcher
October 1996 - February 2016
Humboldt-Universität zu Berlin
Position
  • Professor (Full)

Publications

Publications (446)
Preprint
The skin is the largest human organ with a circadian clock that regulates its function. Although circadian rhythms in specific functions are known, rhythms in the proximal clock output, gene expression, in human skin have not been thoroughly explored. This work reports circadian gene expression in two skin layers, epidermis and dermis, in a cohort...
Preprint
Cdr1as is a conserved circular RNA (circRNA) enriched in the CNS and important for maintaining brain homeostasis. The loss of Cdr1as results in aberrant synaptic transmission and deregulation of stress response and circadian clock genes. However, it is not known whether the expression of Cdr1as or circRNAs, in general, follows a circadian pattern i...
Article
Full-text available
The intestinal epithelium is one of the fastest renewing tissues in mammals. It shows a hierarchical organisation, where intestinal stem cells at the base of crypts give rise to rapidly dividing transit amplifying cells that in turn renew the pool of short-lived differentiated cells. Upon injury and stem-cell loss, cells can also de-differentiate....
Article
Full-text available
Circadian rhythms are biological rhythms with a period close to 24 h. They become entrained to the Earth’s solar day via different periodic cues, so-called zeitgebers. The entrainment of circadian rhythms to a single zeitgeber was investigated in many mathematical clock models of different levels of complexity, ranging from the Poincaré oscillator...
Chapter
Full-text available
Circadian clocks are autonomous systems able to oscillate in a self-sustained manner in the absence of external cues, although such Zeitgebers are typically present. At the cellular level, the molecular clockwork consists of a complex network of interlocked feedback loops. This chapter discusses self-sustained circadian oscillators in the context o...
Preprint
Full-text available
A defining property of circadian clocks is temperature compensation, characterized by the resilience of circadian free-running periods against changes in environmental temperature. As an underlying mechanism, the balance or critical reaction hypothesis have been proposed. While the former supposes a temperature-dependent balancing of reactions with...
Article
Full-text available
Autonomously oscillating circadian clocks resonate with daily environmental (zeitgeber) rhythms to organize physiology around the solar day. While entrainment properties and mechanisms have been studied widely and in great detail for light-dark cycles, entrainment to daily temperature rhythms remains poorly understood despite that they are potent z...
Article
Full-text available
Coupling between cell-autonomous circadian oscillators is crucial to prevent desynchronization of cellular networks and disruption of circadian tissue functions. While neuronal oscillators within the mammalian central clock, the suprachiasmatic nucleus, couple intercellularly, coupling among peripheral oscillators is controversial and the molecular...
Article
Full-text available
The cell biology of circadian clocks is still in its infancy. Here, we describe an efficient strategy for generating knock-in reporter cell lines using CRISPR technology that is particularly useful for genes expressed transiently or at low levels, such as those coding for circadian clock proteins. We generated single and double knock-in cells with...
Preprint
The intestinal epithelium is one of the fastest renewing tissues in mammals with an average turnover time of only a few days. It shows a remarkable degree of stability towards external perturbations such as physical injuries or radiation damage. Tissue renewal is driven by intestinal stem cells, and differentiated cells can de-differentiate if the...
Article
Full-text available
The circadian clock modulates key physiological processes in many organisms. This widespread role of circadian rhythms is typically characterized at the molecular level by profiling the transcriptome at multiple time points. Subsequent analysis identifies transcripts with altered rhythms between control and perturbed conditions, i.e., are different...
Preprint
Full-text available
Autonomously oscillating circadian clocks resonate with daily environmental (zeitgeber) rhythms to organize physiology around the solar day. While entrainment properties and mechanisms have been studied widely and in great detail for light-dark cycles, entrainment to daily temperature rhythms remains poorly understood despite that they are potent z...
Article
Full-text available
Background: Despite the intensive efforts to improve the diagnosis and therapy of sepsis over the last decade, the mortality of septic shock remains high and causes substantial socioeconomical burden of disease. The function of immune cells is time-of-day-dependent and is regulated by several circadian clock genes. This study aims to investigate w...
Chapter
Circadian rhythms are constituted by a complex dynamical system with intertwined feedback loops, molecular switches, and self-sustained oscillations. Mathematical modeling supports understanding available heterogeneous kinetic data, highlights basic mechanisms, and can guide experimental research. Here, we introduce the basic steps from a biologica...
Chapter
Full-text available
RNA interference (RNAi) allows for the selective downregulation of gene expression by neutralizing targeted mRNA molecules and has frequently been used in high-throughput screening endeavors. Here, we describe a protocol for the highly parallel RNAi-mediated downregulation of gene expression in order to search for components involved in circadian r...
Preprint
Full-text available
The circadian clock modulates key physiological processes in many organisms. This widespread role of circadian rhythms is typically characterized at the molecular level by profiling the transcriptome at multiple time points. Subsequent analysis identifies transcripts with altered rhythms between control and perturbed conditions, i.e., are different...
Article
Full-text available
Theory predicts that self-sustained oscillations require robust delays and nonlinearities (ultrasensitivity). Delayed negative feedback loops with switch-like inhibition of transcription constitute the core of eukaryotic circadian clocks. The kinetics of core clock proteins such as PER2 in mammals and FRQ in Neurospora crassa is governed by multipl...
Article
Full-text available
The mammalian circadian clock is well-known to be important for our sleep–wake cycles, as well as other daily rhythms such as temperature regulation, hormone release or feeding–fasting cycles. Under normal conditions, these daily cyclic events follow 24 h limit cycle oscillations, but under some circumstances, more complex nonlinear phenomena, such...
Preprint
Full-text available
Background: Although intensive efforts to improve diagnosis and therapy of sepsis over the last decade, the mortality of septic shock remains high and causes substantial socioeconomical burden of disease. The function of immune cells is time-of-day-dependent and is regulated by several circadian clock genes. This study aims to investigate whether t...
Article
Full-text available
Circadian clocks control rhythms in physiology and behavior entrained to 24 h light–dark cycles. Despite of conserved general schemes, molecular circadian clockworks differ between insect species. With RNA interference (RNAi) we examined an ancient circadian clockwork in a basic insect, the hemimetabolous Madeira cockroach Rhyparobia maderae. With...
Preprint
Full-text available
Theory predicts that self-sustained oscillations require robust delays and nonlinearities (ultrasensitivity). We study the circadian rhythms in the filamentous fungus Neurospora crassa (wild type period 22.5 hours) to investigate the underlying clock mechanisms. Its transcription translation feedback loop (TTFL) includes the activator White Collar...
Article
Full-text available
Entrainment denotes a process of coordinating the internal circadian clock to external rhythmic time-cues (Zeitgeber), mainly light. It is facilitated by stronger Zeitgeber signals and smaller period differences between the internal clock and the external Zeitgeber. The phase of entrainment ψ is a result of this process on the side of the circadian...
Article
Full-text available
Understanding entrainment of circadian rhythms is a central goal of chronobiology. Many factors, such as period, amplitude, Zeitgeber strength, and daylength, govern entrainment ranges and phases of entrainment. We have tested whether simple amplitude-phase models can provide insight into the control of entrainment phases. Using global optimization...
Preprint
Full-text available
The current model of the mammalian circadian oscillator is predominantly based on data from genetics and biochemistry experiments, while the cell biology of circadian clocks is still in its infancy. Here, we describe a new strategy for the efficient generation of knock-in reporter cell lines using CRISPR technology that is particularly useful for l...
Article
Full-text available
Mathematical models of varying complexity have helped shed light on different aspects of circadian clock function. In this work, we question whether minimal clock models (Goodwin models) are sufficient to reproduce essential phenotypes of the clock: a small phase response curve (PRC), fast jetlag and seasonal phase shifts. Instead of building a sin...
Preprint
Full-text available
Understanding entrainment of circadian rhythms is a central goal of chronobiology. Many factors, such as period, amplitude, Zeitgeber strength, and day-length, govern entrainment ranges and the phase of entrainment. Using global optimization, we derive conceptual models with just three free parameters (period, amplitude, relaxation rate) that repro...
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Preprint
Full-text available
Mathematical models of varying complexity have helped shed light on different aspects of circadian clock function. In this work, we question whether minimal clock models (Goodwin models) are sufficient to reproduce essential phenotypes of the clock: a small phase response curve (PRC), fast jetlag and seasonal phase shifts. Instead of building a sin...
Article
Full-text available
Circadian rhythms are generated by interlocked transcriptional-translational negative feedback loops (TTFLs), the molecular process implemented within a cell. The contributions, weighting and balancing between the multiple feedback loops remain debated. Dissociated, free-running dynamics in the expression of distinct clock genes has been described...
Article
Full-text available
The circadian clock of the nocturnal Madeira cockroach is located in the accessory medulla, a small non-retinotopic neuropil in the brain’s visual system. The clock comprises about 240 neurons that control rhythms in physiology and behaviour such as sleep-wake cycles. The clock neurons contain an abundant number of partly co-localized neuropeptides...
Article
Full-text available
Autonomous endogenous time-keeping is ubiquitous across many living organisms, known as the circadian clock when it has a period of about 24 h. Interestingly, the fundamental design principle with a network of interconnected negative and positive feedback loops is conserved through evolution, although the molecular components differ. Filamentous fu...
Preprint
Full-text available
An autonomous endogenous time-keeping is ubiquitous across many living organisms known as circadian clock when it has a period of about 24 hours. Interestingly, the fundamental design principle with a network of interconnected negative and positive feedback loops is conserved through evolution, although the molecular components differ. Filamentous...
Article
Full-text available
The circadian clock is an endogenous oscillator that controls daily rhythms in metabolism, physiology, and behavior. Although the timekeeping components differ among species, a common design principle is a transcription-translation negative feedback loop. However, it is becoming clear that other mechanisms can contribute to the generation of 24 h r...
Preprint
An autonomous endogenous time-keeping is ubiquitous across many living organisms known as circadian clock when it has a period of about 24 hours. Interestingly, the fundamental design principle with a network of interconnected negative and positive feedback loops is conserved through evolution, although the molecular components differ. Filamentous...
Preprint
Full-text available
The circadian clock is an endogenous oscillator that controls daily rhythms in metabolism, physiology and behavior. Although the timekeeping components differ among species, a common design principle is a transcription-translation negative feedback loop. However, it is becoming clear that other mechanisms can contribute to the generation of 24 h rh...
Preprint
The circadian clock is the molecular mechanism responsible for the adaptation to daily rhythms in living organisms. Oscillations and fluctuations in environmental conditions regulate the circadian clock through signaling pathways. We study the response to continuous photic perturbations in a minimal molecular network model of the circadian clock, c...
Preprint
Full-text available
Circadian rhythms are generated by interlocked transcriptional-translational negative feedback loops (TTFLs), the molecular process implemented within a cell. The contributions, weighting and balancing between the multiple feedback loops remain debated. Dissociated, free-running dynamics in the expression of distinct clock genes has been described...
Article
Full-text available
Circadian clocks are autonomous oscillators driving daily rhythms in physiology and behavior. In mammals, a network of coupled neurons in the suprachiasmatic nucleus (SCN) is entrained to environmental light-dark cycles and orchestrates the timing of peripheral organs. In each neuron, transcriptional feedbacks generate noisy oscillations. Coupling...
Data
Table S2. Functional and KEGG Pathway Enrichment of the Third Harmonic Genes, Related to Figure 1 Assignment of the third harmonic genes to the significant (p < 0.05) functional categories identified by FungiFun2. The results of a similar enrichment analysis of third harmonic genes in the KEGG pathways are also shown.
Data
Table S1. Circadian and Harmonic Genes Identified in the WT N. crassa Strain, Related to Figures 1 and S1 Lists of the harmonic genes identified in the original and verification datasets along with the amplitude and phase of the rhythms and presence of binding sites of known transcription factors in the vicinity of the gene.
Article
Full-text available
In many organisms, the circadian clock drives rhythms in the transcription of clock-controlled genes that can be either circadian (∼24-hr period) or ultradian (<24-hr period). Ultradian rhythms with periods that are a fraction of 24 hr are termed harmonics. Several harmonic transcripts were discovered in the mouse liver, but their functional signif...
Article
Background: The circadian clock is a fundamental and pervasive biological program that coordinates 24-hour rhythms in physiology, metabolism and behaviour, and it is essential to health. Whereas time-of-day adapted therapy is increasingly reported to be highly success-ful, it needs to be personalized since internal circadian time is different for...
Article
Full-text available
Gene regulatory feedback loops generate autonomous circadian rhythms in mammalian tissues. The well-studied core clock network contains many negative and positive regulations. Multiple feedback loops have been discussed as primary rhythm generators but the design principles of the core clock and differences between tissues are still under debate. H...
Preprint
Full-text available
Gene regulatory feedback loops generate autonomous circadian rhythms in mammalian tissues. The well-studied core clock network contains many negative and positive regulations. Multiple feedback loops have been discussed as primary rhythm generators but the design principles of the core clock and differences between tissues are still under debate. H...
Data
Created on Mathematica 11 in 2016. Output formatting and period estimation requires PMTAnalysis.m package, available at GitHub, SourceForge, and ResearchGate. Relevant figure legend: Fig. 3 g–i The twist coupling model recaptures the acceleration of the circadian oscillation and increase in amplitude by coupling. In the simulation, results from fi...
Article
Full-text available
Mammalian circadian clocks have a hierarchical organization, governed by the suprachiasmatic nucleus (SCN) in the hypothalamus. The brain itself contains multiple loci that maintain autonomous circadian rhythmicity, but the contribution of the non-SCN clocks to this hierarchy remains unclear. We examine circadian oscillations of clock gene expressi...
Article
Full-text available
Body temperature rhythms synchronize circadian oscillations in different tissues, depending on the degree of cellular coupling: the responsiveness to temperature is higher when single circadian oscillators are uncoupled. So far, the role of coupling in temperature responsiveness has only been studied in organotypic tissue slices of the central circ...
Data
PER2::LUC bioluminescence of a mouse suprachiasmatic nucleus dispersal culture exposed to a T20-temperature cycle with deltaT = 2K. The recording time in days is depicted in the top right corner. Culture temperature is shown in the bottom right corner. (MP4)
Data
PER2::LUC bioluminescence of mouse primary fibroblasts exposed to a T20-temperature cycle with deltaT = 4K. The recording time in days is depicted in the top right corner. Culture temperature is shown in the bottom right corner. PER2::LUC fibroblasts were mixed with C57Bl/6 WT fibroblasts at a ratio of about 1:20, and cultures were grown to conflue...
Data
PER2::LUC bioluminescence of mouse primary fibroblasts exposed to a T24-temperature cycle with deltaT = 4K. The recording time in days is depicted in the top right corner. Culture temperature is shown in the bottom right corner. PER2::LUC fibroblasts were mixed with C57Bl/6 WT fibroblasts at a ratio of about 1:20, and cultures were grown to conflue...
Chapter
Eukaryotic genes are typically regulated by multiple transcription factors in a combinatorial manner. Quantitative understanding of gene regulation is particularly relevant for oscillatory expression due to transcriptional feedback loops. For periodic gene expression, the phases are essential for physiological functions.In our project we combine bi...
Article
Full-text available
Modern imaging techniques allow the monitoring of circadian rhythms of single cells. Coupling between these single cellular circadian oscillators can generate coherent periodic signals on the tissue level that subsequently orchestrate physiological outputs. The strength of coupling in such systems of oscillators is often unclear. In particular, eff...
Article
Full-text available
Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational...
Article
Full-text available
Motivation: Neural activities of the brain occur through the formation of spatio-temporal patterns. In recent years, macroscopic neural imaging techniques have produced a large body of data on these patterned activities, yet a numerical measure of spatio-temporal coherence has often been reduced to the global order parameter, which does not uncove...
Article
Full-text available
Cellular signaling systems precisely transmit information in the presence of molecular noise while retaining flexibility to accommodate the needs of individual cells. To understand design principles underlying such versatile signaling, we analyzed the response of the tumor suppressor p53 to varying levels of DNA damage in hundreds of individual cel...