Biology subjects

del Olmo, M.

Publications and source records attributed to del Olmo, M..

5 recordsLinked to original sources

bioRxiv2023

Are circadian amplitudes and periods correlated? A new twist in the story

Three parameters are important to characterize a circadian and in general any biological clock: period, phase and amplitude. While circadian periods have been shown to correlate with entrainment phases, and clock amplitude influences the phase response of an oscillator to pulse-like zeitgeber signals, the co-modulations of amplitude and periods, which we term twist, have not been studied in detail. In this paper we define two concepts: parametric twist refers to amplitude-period correlations arising in ensembles of self-sustained clocks in the absence of external inputs, and phase space twist refers to the co-modulation of an individual clocks amplitude and period in response to external zeitgebers. Our findings show that twist influences the interaction of oscillators with the environment, facilitating entrainment, fastening recovery to pulse-like perturbations or modifying the response of an individual clock to coupling. This theoretical framework might be applied to understand the emerging properties of other oscillating systems.

molecular biology↗

bioRxiv2023

Coupling allows robust redox circadian rhythms despite heterogeneity and noise

Circadian clocks are endogenous oscillators present in almost all cells that drive daily rhythms in physiology and behavior. There are two mechanisms that have been proposed to explain how circadian rhythms are generated in mammalian cells: through a transcription-translation feedback loop (TTFL) and based on oxidation/reduction reactions, both of which are intrinsically stochastic and heterogeneous at the single cell level. In order to explore the emerging properties of stochastic and heterogeneous redox oscillators, we simplify a recently developed kinetic model of redox oscillations to an amplitude-phase oscillator with twist (period-amplitude correlation) and subject to Gaussian noise. We show that noise and heterogeneity alone lead to fast desynchronization, and that coupling between noisy oscillators can establish robust and synchronized rhythms with amplitude expansions and tuning of the period due to twist. Coupling a network of redox oscillators to a simple model of the TTFL also contributes to synchronization, large amplitudes and fine-tuning of the period for appropriate interaction strengths. These results provide insights into how the circadian clock compensates randomness from intracellular sources and highlight the importance of noise, heterogeneity and coupling in the context of circadian oscillators.

systems biology↗

bioRxiv2022

Inter-layer and inter-subject variability of circadian gene expression in human skin

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 of young, healthy adults, who maintained natural, regular sleep schedules. 10% of the expressed genes showed rhythms at the population level, of which only a third differed between the two layers. Broadly, expression magnitudes of circadian genes were consistent across subjects in each layer. Amplitude and phases of circadian gene expression, however, varied more across subjects than layers, with amplitude being more variable than phases. Expression amplitudes in the epidermis were larger and more subject-variable, while they were smaller and more consistent in the dermis. Core clock gene expression was similar across layers at the population-level, but were heterogeneous in the their variability across subjects. We used this data to identify small sets of biomarkers for internal clock phase in each layer, which consisted of layer-specific non-core clock genes. This work provides a valuable resource to advance our understanding of human skin to realize the potential of circadian medicine as well as a novel methodology to quantify sources of variability in human circadian rhythms.

bioinformatics↗

bioRxiv2020

Live-cell imaging of circadian clock protein dynamics in CRISPR-generated knock-in cells

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 lowly or transiently expressed genes, such as those coding for circadian clock proteins. We generated single and double knock-in cells with endogenously expressed PER2 and CRY1 fused to fluorescent proteins, which allowed to simultaneously monitor the dynamics of CRY1 and PER2 proteins in live single cells. Both proteins are highly rhythmic in the nucleus of human cells with PER2 showing a much higher amplitude than CRY1. Surprisingly, CRY1 protein is nuclear at all circadian times indicating the absence of circadian gating of nuclear import. Furthermore, in the nucleus of individual cells CRY1 abundance rhythms are phase-delayed ([~]5 hours), and CRY1 levels are much higher (>6 times) compared to PER2 questioning the current model of the circadian oscillator. Our knock-in strategy will allow the generation of additional single, double or triple knock-in cells for circadian clock proteins, which should greatly advance our understanding about the cell biology of circadian clocks.

cell biology↗

bioRxiv2019

A Robust Model for Circadian Redox Oscillations

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 rhythms. In mammalian adrenal gland, heart and brown adipose tissue, peroxiredoxins (Prx) exhibit 24 h rhythms in their redox state. Such rhythms are generated as a result of an inactivating hyperoxidation reaction that is reduced by coordinated import of the sulfiredoxin (Srx) into the mitochondria. However, a quantitative description of the Prx/Srx oscillating system is still missing. We investigate the basic principles that generate mitochondrial Prx/Srx rhythms using computational modeling. We observe that the previously described delay in mitochondrial Srx import, in combination with an appropriate separation of fast and slow reactions is sufficient to generate robust self-sustained relaxation-like oscillations. We find that our conceptual model can be regarded as a series of three consecutive phases and two temporal switches, highlighting the importance of delayed negative feedback and switches in the generation of oscillations.

molecular biology↗