Circadian Yin-Yang Regulation and Its Manipulation to Globally Reprogram Gene Expression

Abstract

Summary Background The cyanobacterial circadian program exerts genome-wide control of gene expression. KaiC undergoes rhythms of phosphorylation that are regulated by interactions with KaiA and KaiB. The phosphorylation status of KaiC is thought to mediate global transcription via output factors SasA, CikA, LabA, RpaA, and RpaB. Overexpression of kaiC has been reported to globally repress gene expression. Results Here we show that the positive circadian component KaiA upregulates “subjective dusk” genes and its overexpression de-activates rhythmic gene expression without significantly affecting growth rates in constant light. We analyze the global patterns of expression that are regulated by KaiA versus KaiC and find in contrast to the previous report of KaiC repression that there is a “Yin-Yang” regulation of gene expression whereby kaiA overexpression activates “dusk genes” and represses “dawn genes,” whereas kaiC overexpression complementarily activates “dawn genes” and represses “dusk genes.” Moreover, continuous induction of kaiA latched KaiABC-regulated gene expression to provide constitutively increased transcript levels of diverse endogenous and heterologous genes that are expressed in the predominant “subjective dusk” phase. In addition to analyzing KaiA regulation of endogenous gene expression, we apply these insights to the expression of heterologous proteins whose products are of potential value, namely human proinsulin, foreign luciferase, and exogenous hydrogenase. Conclusions Both KaiC and KaiA complementarily contribute to the regulation of circadian gene expression via Yin-Yang switching. Circadian patterns can be reprogrammed by overexpression of kaiA or kaiC to constitutively enhance gene expression, and this reprogramming can improve 24/7 production of heterologous proteins that are useful as pharmaceuticals or biofuels.

Culturing Synechocystis sp. Strain PCC 6803 with N 2 and CO 2 in a Diel Regime Reveals Multiphase Glycogen Dynamics with Low Maintenance Costs

“…Whether engineered metabolic routes result in high rates of product formation depends on the metabolic flux capacities, the proper regulatory signals, and the availability of the intracellular substrate(s). Hence, the productivity of cyanobacteria is highly dependent on the changes of their metabolite levels and/or regulation of metabolism during the daily cycle (2)(3)(4)(5). Rhythms of the metabolism are affected by the light-dark transitions and also by the circadian clock, both with distinct effects (6).…”

Interplay between cellular redox oscillations and circadian clocks

“…Humans may have selected over time a strain devoid of a clock, which would be more efficient in the constant and highly nutrient saturated conditions typically used for winemaking and brewing. In agreement with this interpretation, pausing of the cyanobacterial clock enhances the production of proteins and hydrogen by these photosynthetic organisms in constant light [101]. However, it is still not clear why yeast would need nutrient-limiting conditions to exhibit population-level oscillations, but synchronization between single-cell oscillators may be a key determinant [102,103].…”

“…and hydrogen by these photosynthetic organisms in constant light [101]. However, it is still not clear why yeast would need nutrient-limiting conditions to exhibit population-level oscillations, but synchronization between single-cell oscillators may be a key determinant [102,103].…”

“…Canonical transcriptional oscillations are the first layer of molecular oscillations, enabling the cell to organize its physiology around the 24-h cycle. The transcriptional oscillations interact with underlying redox and metabolic cycles, which would be the fundamental drivers of circadian self-sustained oscillations.and hydrogen by these photosynthetic organisms in constant light [101]. However, it is still not clear why yeast would need nutrient-limiting conditions to exhibit population-level oscillations, but synchronization between single-cell oscillators may be a key determinant [102,103].…”

Estimating the Yin-Yang Nature of Western Herbs: A Potential Tool Based on Antioxidation- Oxidation Theory

“…They are different in nature (Yin or Yang), temperature (cold or hot), strength and speed of action. The dual Yin-Yang concept is more and more used by the scientists also, in order to describe the balance/disbalance of various biological or biochemical processes, such as immunoregulation, autoimmunity, inflammation (Mills et al, 2004;Zhang, 2007), gene expression (Xu et al, 2013), cause and development of cancer (Wang et al, 2004). During recent years, new advances in the field of Yin-Yang biochemical correspondences have led to the conclusion that Yin might refer to antioxidation and Yang to oxidation (Ou et al, 2003;Szeto et al, 2004; Ko et al, 2006).…”