scholarly journals The cyanobacterial circadian clock follows midday in vivo and in vitro

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Eugene Leypunskiy ◽  
Jenny Lin ◽  
Haneul Yoo ◽  
UnJin Lee ◽  
Aaron R Dinner ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Scaling Law ◽  
Clock Cycle ◽  
Circadian Clocks ◽  
Day Length ◽  
Mathematical Framework ◽  
Simple Scaling ◽  
Biochemical Oscillator

Circadian rhythms are biological oscillations that schedule daily changes in physiology. Outside the laboratory, circadian clocks do not generally free-run but are driven by daily cues whose timing varies with the seasons. The principles that determine how circadian clocks align to these external cycles are not well understood. Here, we report experimental platforms for driving the cyanobacterial circadian clock both in vivo and in vitro. We find that the phase of the circadian rhythm follows a simple scaling law in light-dark cycles, tracking midday across conditions with variable day length. The core biochemical oscillator comprised of the Kai proteins behaves similarly when driven by metabolic pulses in vitro, indicating that such dynamics are intrinsic to these proteins. We develop a general mathematical framework based on instantaneous transformation of the clock cycle by external cues, which successfully predicts clock behavior under many cycling environments.

scholarly journals Circadian clock control of eIF2α phosphorylation is necessary for rhythmic translation initiation

2020 ◽  
Vol 117 (20) ◽  
pp. 10935-10945 ◽  
Author(s):  
Shanta Karki ◽  
Kathrina Castillo ◽  
Zhaolan Ding ◽  
Olivia Kerr ◽  
Teresa M. Lamb ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Translation Initiation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Nutrient Metabolism ◽  
Eif2α Phosphorylation ◽  
Eif2α Kinase ◽  
The Impact

The circadian clock in eukaryotes controls transcriptional and posttranscriptional events, including regulation of the levels and phosphorylation state of translation factors. However, the mechanisms underlying clock control of translation initiation, and the impact of this potential regulation on rhythmic protein synthesis, were not known. We show that inhibitory phosphorylation of eIF2α (P-eIF2α), a conserved translation initiation factor, is clock controlled in Neurospora crassa, peaking during the subjective day. Cycling P-eIF2α levels required rhythmic activation of the eIF2α kinase CPC-3 (the homolog of yeast and mammalian GCN2), and rhythmic activation of CPC-3 was abolished under conditions in which the levels of charged tRNAs were altered. Clock-controlled accumulation of P-eIF2α led to reduced translation during the day in vitro and was necessary for the rhythmic synthesis of select proteins in vivo. Finally, loss of rhythmic P-eIF2α levels led to reduced linear growth rates, supporting the idea that partitioning translation to specific times of day provides a growth advantage to the organism. Together, these results reveal a fundamental mechanism by which the clock regulates rhythmic protein production, and provide key insights into how rhythmic translation, cellular energy, stress, and nutrient metabolism are linked through the levels of charged versus uncharged tRNAs.

scholarly journals Hierarchy and extremes in selections from pools of randomized proteins

2016 ◽  
Vol 113 (13) ◽  
pp. 3482-3487 ◽  
Author(s):  
Sébastien Boyer ◽  
Dipanwita Biswas ◽  
Ananda Kumar Soshee ◽  
Natale Scaramozzino ◽  
Clément Nizak ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Scaling Law ◽  
Natural Populations ◽  
Value Theory ◽  
Darwinian Evolution ◽  
Future Evolution ◽  
Synthetic Protein ◽  
Simple Scaling ◽  
Protein Libraries

Variation and selection are the core principles of Darwinian evolution, but quantitatively relating the diversity of a population to its capacity to respond to selection is challenging. Here, we examine this problem at a molecular level in the context of populations of partially randomized proteins selected for binding to well-defined targets. We built several minimal protein libraries, screened them in vitro by phage display, and analyzed their response to selection by high-throughput sequencing. A statistical analysis of the results reveals two main findings. First, libraries with the same sequence diversity but built around different “frameworks” typically have vastly different responses; second, the distribution of responses of the best binders in a library follows a simple scaling law. We show how an elementary probabilistic model based on extreme value theory rationalizes the latter finding. Our results have implications for designing synthetic protein libraries, estimating the density of functional biomolecules in sequence space, characterizing diversity in natural populations, and experimentally investigating evolvability (i.e., the potential for future evolution).

scholarly journals Cell type resolved co-expression networks of core clock genes in brain development

2021 ◽  
Author(s):  
Surbhi Sharma ◽  
Asgar Hussain Ansari ◽  
Soundhar Ramasamy
Keyword(s):  
Circadian Clock ◽  
Single Cell ◽  
Radial Glia ◽  
Clock Genes ◽  
Neuronal Cell ◽  
Cell Types ◽  
Developing Brain ◽  
Knock Out

AbstractThe circadian clock regulates vital cellular processes by adjusting the physiology of the organism to daily changes in the environment. Rhythmic transcription of core Clock Genes (CGs) and their targets regulate these processes at the cellular level. Circadian clock disruption has been observed in people with neurodegenerative disorders like Alzheimer’s and Parkinson’s. Also, ablation of CGs during development has been shown to affect neurogenesis in both in vivo and in vitro models. Previous studies on the function of CGs in the brain have used knock-out models of a few CGs. However, a complete catalog of CGs in different cell types of the developing brain is not available and it is also tedious to obtain. Recent advancements in single-cell RNA sequencing (scRNA-seq) has revealed novel cell types and elusive dynamic cell states of the developing brain. In this study by using publicly available single-cell transcriptome datasets we systematically explored CGs-coexpressing networks (CGs-CNs) during embryonic and adult neurogenesis. Our meta-analysis reveals CGs-CNs in human embryonic radial glia, neurons and also in lesser studied non-neuronal cell types of the developing brain.

scholarly journals Effects of caffeine on the human circadian clock in vivo and in vitro

2015 ◽  
Vol 7 (305) ◽  
pp. 305ra146-305ra146 ◽  
Author(s):  
Tina M. Burke ◽  
Rachel R. Markwald ◽  
Andrew W. McHill ◽  
Evan D. Chinoy ◽  
Jesse A. Snider ◽  
...  
Keyword(s):  
Circadian Clock

scholarly journals Photoperiodic regulation of prolactin secretion: changes in intra-pituitary signalling and lactotroph heterogeneity

2004 ◽  
Vol 180 (3) ◽  
pp. 351-356 ◽  
Author(s):  
JD Johnston
Keyword(s):  
Environmental Conditions ◽  
Seasonal Changes ◽  
Mammalian Species ◽  
Prolactin Secretion ◽  
Day Length ◽  
Pars Tuberalis ◽  
Photoperiodic Regulation ◽  
Pituitary Lactotroph

Many mammalian species utilise day-length (photoperiod) to adapt their physiology to seasonal changes in environmental conditions, via secretion of pineal melatonin. Photoperiodic regulation of prolactin secretion is believed to occur via melatonin-mediated changes in the secretion of a putative prolactin secretagogue, tuberalin, from the pituitary pars tuberalis. Despite the in vivo and in vitro evidence in support of this intra-pituitary signalling mechanism, the identity of tuberalin has yet to be elucidated. This paper reviews recent advances in the characterisation of tuberalin and the regulation of its secretion. Furthermore, the hypothesis that pituitary lactotroph cells display heterogeneity in their response to changing photoperiod and tuberalin secretion is examined.

scholarly journals Sympathetic Activation Induces Skeletal Fgf23 Expression in a Circadian Rhythm-dependent Manner

2013 ◽  
Vol 289 (3) ◽  
pp. 1457-1466 ◽  
Author(s):  
Masanobu Kawai ◽  
Saori Kinoshita ◽  
Shigeki Shimba ◽  
Keiichi Ozono ◽  
Toshimi Michigami
Keyword(s):  
Food Intake ◽  
Circadian Clock ◽  
Sympathetic Tone ◽  
Dark Phase ◽  
Dependent Manner ◽  
Phosphate Metabolism ◽  
Sympathetic Activation ◽  
Clock Network

The circadian clock network is well known to link food intake and metabolic outputs. Phosphorus is a pivotal nutritional factor involved in energy and skeletal metabolisms and possesses a circadian profile in the circulation; however, the precise mechanisms whereby phosphate metabolism is regulated by the circadian clock network remain largely unknown. Because sympathetic tone, which displays a circadian profile, is activated by food intake, we tested the hypothesis that phosphate metabolism was regulated by the circadian clock network through the modification of food intake-associated sympathetic activation. Skeletal Fgf23 expression showed higher expression during the dark phase (DP) associated with elevated circulating FGF23 levels and enhanced phosphate excretion in the urine. The peaks in skeletal Fgf23 expression and urine epinephrine levels, a marker for sympathetic tone, shifted from DP to the light phase (LP) when mice were fed during LP. Interestingly, β-adrenergic agonist, isoproterenol (ISO), induced skeletal Fgf23 expression when administered at ZT12, but this was not observed in Bmal1-deficient mice. In vitro reporter assays revealed that ISO trans-activated Fgf23 promoter through a cAMP responsive element in osteoblastic UMR-106 cells. The mechanism of circadian regulation of Fgf23 induction by ISO in vivo was partly explained by the suppressive effect of Cryptochrome1 (Cry1) on ISO signaling. These results indicate that the regulation of skeletal Fgf23 expression by sympathetic activity is dependent on the circadian clock system and may shed light on new regulatory networks of FGF23 that could be important for understanding the physiology of phosphate metabolism.

scholarly journals Disruption of the Circadian Clock Alters Antioxidative Defense via the SIRT1-BMAL1 Pathway in 6-OHDA-Induced Models of Parkinson’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Yali Wang ◽  
Dongjun Lv ◽  
Wenwen Liu ◽  
Siyue Li ◽  
Jing Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Circadian Clock ◽  
Antioxidative Activity ◽  
Expression Patterns ◽  
Antioxidative Defense ◽  
Real Time Quantitative Pcr ◽  
6 Hydroxydopamine

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is known to involve circadian dysfunction and oxidative stress. Although antioxidative defense is regulated by the molecular circadian clock, few studies have examined their function in PD and their regulation by silent information regulator 1 (SIRT1). We hypothesize that reduced antioxidative activity in models of PD results from dysfunction of the molecular circadian clock via the SIRT1 pathway. We treated rats and SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) and measured the expression of core circadian clock and associated nuclear receptor genes using real-time quantitative PCR as well as levels of SIRT1, brain and muscle Arnt-like protein 1 (BMAL1), and acetylated BMAL1 using Western blotting. We found that 6-OHDA treatment altered the expression patterns of clock and antioxidative molecules in vivo and in vitro. We also detected an increased ratio of acetylated BMAL1:BMAL1 and a decreased level of SIRT1. Furthermore, resveratrol, an activator of SIRT1, decreased the acetylation of BMAL1 and inhibited its binding with CRY1, thereby reversing the impaired antioxidative activity induced by 6-OHDA. These results suggest that a dysfunctional circadian clock contributes to an abnormal antioxidative response in PD via a SIRT1-dependent BMAL1 pathway.

scholarly journals Circadian Rhythm Is Disrupted by ZNF704 in Breast Carcinogenesis

2020 ◽  
Author(s):  
Chao Yang ◽  
Jiajing Wu ◽  
Xinhua Liu ◽  
Yue Wang ◽  
Beibei Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Circadian Clock ◽  
Copy Number Gain ◽  
Breast Carcinogenesis ◽  
Breast Cancer Patients ◽  
Genome Wide ◽  
Important Regulator ◽  
High Level

AbstractCopy number gain in chromosome 8q21 is considered as the prototype of genetic abnormalities associated with development of breast cancer, yet the oncogenic potential underlying this amplicon in breast carcinogenesis remains to be delineated. We report here that ZNF704, a gene mapped to 8q21, is recurrently amplified in various malignancies including breast cancer. We found that ZNF704 acts as transcription repressor and interacts with the transcription corepressor SIN3A complex. Genome-wide interrogation of the transcriptional targets identifies that the ZNF704/SIN3A complex represses a panel of genes including PER2 that are critically involved in the function of circadian clock. Indeed, ZNF704 overexpression prolongs the period and dampens the amplitude of circadian clock. We showed that ZNF704 promotes the proliferation and invasion of breast cancer cells in vitro and accelerates the growth and metastasis of breast cancer in vivo. Consistently, the level of ZNF704 expression is inversely correlated with that of PER2 in breast carcinomas, and high level of ZNF704 correlates with advanced histological grades, lymph node positivity, and poor prognosis of breast cancer patients, especially those with HER2+ and basal-like subtypes. These results indicate that ZNF704 is an important regulator of circadian clock and a potential driver for breast carcinogenesis.

scholarly journals A role for the circadian clock protein Per1 in the regulation of aldosterone levels and renal Na+ retention

2013 ◽  
Vol 305 (12) ◽  
pp. F1697-F1704 ◽  
Author(s):  
Jacob Richards ◽  
Kit-Yan Cheng ◽  
Sean All ◽  
George Skopis ◽  
Lauren Jeffers ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Circadian Clock ◽  
Target Genes ◽  
Collecting Duct ◽  
Specific Rate ◽  
Wild Type ◽  
Α Subunit ◽  
Aldosterone Production

The circadian clock plays an important role in the regulation of physiological processes, including renal function and blood pressure. We have previously shown that the circadian protein period (Per)1 regulates the expression of multiple Na+ transport genes in the collecting duct, including the α-subunit of the renal epithelial Na+ channel. Consistent with this finding, Per1 knockout mice exhibit dramatically lower blood pressure than wild-type mice. We have also recently demonstrated the potential opposing actions of cryptochrome (Cry)2 on Per1 target genes. Recent work by others has demonstrated that Cry1/2 regulates aldosterone production through increased expression of the adrenal gland-specific rate-limiting enzyme 3β-dehydrogenase isomerase (3β-HSD). Therefore, we tested the hypothesis that Per1 plays a role in the regulation of aldosterone levels and renal Na+ retention. Using RNA silencing and pharmacological blockade of Per1 nuclear entry in the NCI-H295R human adrenal cell line, we showed that Per1 regulates 3β-HSD expression in vitro. These results were confirmed in vivo: mice with reduced levels of Per1 had decreased levels of plasma aldosterone and decreased mRNA expression of 3β-HSD. We postulated that mice with reduced Per1 would have a renal Na+-retaining defect. Indeed, metabolic cage experiments demonstrated that Per1 heterozygotes excreted more urinary Na+ compared with wild-type mice. Taken together, these data support the hypothesis that Per1 regulates aldosterone levels and that Per1 plays an integral role in the regulation of Na+ retention.

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