Collective behavior in gene regulation: The cell is an oscillator, the cell cycle a developmental process

Abstract

The finding of a genome-wide oscillation in transcription that gates cells into S phase and coordinates mitochondrial and metabolic functions has altered our understanding of how the cell cycle is timed and how stable cellular phenotypes are maintained. Here we present the evidence and arguments in support of the idea that everything oscillates, and the rationale for viewing the cell as an attractor from which deterministic noise can be tuned by appropriate coupling among the many feedback loops, or regulons, that make up the transcriptional-respiratory attractor cycle. The existence of this attractor also explains many of the dynamic macroscopic properties of the cell cycle and appears to be the timekeeping oscillator in both cell cycles and circadian rhythms. The path taken by this primordial oscillator in the course of differentiation or drug response may involve period-doubling behavior. Evidence for a relatively high-frequency timekeeping oscillator in yeast and mammalian cells comes from expression array analysis, and GC/MS in the case of yeast, and primarily from macroscopic measures of phase response to perturbation in the case of mammalian cells. Low-amplitude, genome-wide oscillations, a ubiquitous but often unrecognized attribute of phenotype, may be a source of seemingly intractable biological noise in microarray and proteomic studies. These oscillations in transcript and protein levels and the repeated cycles of synthesis and degradation they require, represent a high energy cost to the cell which must, from an evolutionary point of view, be recovered as essential information. We suggest that the information contained in this genome-wide oscillation is the dynamic code that organizes a stable phenotype from an otherwise passive genome.

Probabilistic Epigenesis and Modern Behavioral and Neural Genetics

“…Instead, they seem to extend into every domain of neural and behavioral functioning. The entire genome appears to be dynamic and show cycles of activity (Klevecz, Li, Marcus, & Frankel, 2008). For those who have devoted a career to the study of development, this all makes good sense.…”

Determining biological noise via single cell analysis

“…It is the temporal variation in the GRF outputs that ultimately defines cell size, cell cycle frequency or status, developmental cell-fate decisions [15], the production of biomolecules such as mRNA [16], and the release of species such as Ca 2+ [17]. The form of the GRF output varies among biological systems and they may appear as a steady function, a gradual change, on–off switching [15, 18], bursts [19], oscillations [20, 21], or circadian clocks [22, 23]. Therefore, the noise associated with each GRF output is similarly time-dependent.…”

Period doubling induced by thermal noise amplification in genetic circuits

“…This phenomenon is observed in a wide range of scales and can be found, for example, in the arrhythmia of cardiac functions4, or in the firing of neurons56, where it has been tentatively explained on the basis of the well know bifurcation to chaos paradigm910, or in the distribution of population growth in yeast12, where it was ascribed to genetic regulatory circuits. Period doubling has also been observed during cell divisions and circadian cycles, where it can manifest spontaneously11 or in response to chemical perturbations13. Similarly, it has been shown that the genome-wide transcriptional oscillation in yeast can experience period doubling in reaction to drugs14.…”