Systems biology of cellular rhythms

Abstract

a b s t r a c tRhythms abound in biological systems, particularly at the cellular level where they originate from the feedback loops present in regulatory networks. Cellular rhythms can be investigated both by experimental and modeling approaches, and thus represent a prototypic field of research for systems biology. They have also become a major topic in synthetic biology. We review advances in the study of cellular rhythms of biochemical rather than electrical origin by considering a variety of oscillatory processes such as Ca ++ oscillations, circadian rhythms, the segmentation clock, oscillations in p53 and NF-jB, synthetic oscillators, and the oscillatory dynamics of cyclin-dependent kinases driving the cell cycle. Finally we discuss the coupling between cellular rhythms and their robustness with respect to molecular noise. Ó 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. The unfolding of cellular rhythmsOscillatory behavior represents one of the most conspicuous properties of life [1][2][3]. Periodic processes indeed underlie a variety of key physiological functions such as the sleep-wake cycle controlled by circadian rhythms, heart beating, brain rhythmic activity, respiration, hormone pulsatile secretion, and ovulation, to mention but a few. A large number of biological rhythms originate at the cellular level. The main reason why rhythmic behavior is so frequently encountered is related to the existence of feedback processes, which control the dynamics of organisms at the cellular and supracellular levels. Oscillations are clearly a systemic property, associated with regulatory interactions between the constitutive elements of biological systems, which may range from metabolic and genetic networks to cell and animal populations. Rhythmic phenomena therefore represent a prototypic field of research in systems biology. In line with the development of systems biology, rhythms have been approached, from the very beginning, both from an experimental and a modeling perspective [1,2].Before examining in more detail the mechanism of cellular rhythms in the light of systems biology, it is useful to briefly sketch the chronological development of the field which, starting from dissociated observations, is converging to a view that unifies oscillations observed in a variety of contexts at the cellular level, in spite of the differences in period and underlying molecular mechanism. If we look at the progress of research on the molecular mechanism of cellular rhythms, it is convenient to consider its unfolding decade by decade, by listing major developments. Rhythms in the electrical activity of muscles and neurons are known experimentally for more than one hundred years, but the development of studies on their ionic mechanism dates back to the 1950s. Despite the importance of cellular rhythms of electrical nature, the present review will focus on cellular rhythms that are not electrical and originate from cellular regulations other than those that pertain to the control of voltage-gate...

In Vivo Tissue-wide Synchronization of Mitochondrial Metabolic Oscillations

“…Our findings underscore the fact that in the native tissue the complex integration of signals coming from the vasculature, the nervous system, the tissue microenvironment, and the surrounding cells, ensure the proper conditions to maintain mitochondrial metabolism in an oscillatory modality (Kim et al, 2010). A major advantage for cell metabolism to adopt an oscillatory behavior is that oscillations are a more favorable dynamic status to rapidly respond to sudden changes in the environment and energy demand (Goldbeter et al, 2012; Kruse and Julicher, 2005; Richter and Ross, 1981). …”

Protein sequestration versus Hill‐type repression in circadian clock models

“…Besides circadian clocks, there are many other biological oscillators [178] such as segmentation clocks [179,180], cell cycle oscillators [181][182][183], p53 oscillators [184,185], and synthetic oscillators [186,187]. While Hill-type regulations have frequently been used in models of these biological oscillators [188][189][190][191][192][193][194][195][196], the critical roles of protein sequestration were also reported [71,197].…”

Complex, non-monotonic dose-response curves with multiple maxima: Do we (ever) sample densely enough?

“…circadian clocks, cell cycle oscillators) and space (e.g., periodic waves of Dictyostelium cells aggregation, embryonic patterning). [19][20][21][22] However, theoretical models -for example those of eukaryotic cell cycle regulation 23 or of effects of glucose concentration on glucose-regulated miRNA levels in tumor cells 24 -show that some parameters of a system of metabolic reactions mutually linked by regulatory feedback relationships may also exhibit complex, non-monotonic responses as a function of parameters other than time or space, such as e.g. cell size or concentration of one of the systems components.…”