scholarly journals Comment on “Circadian rhythms in the absence of the clock gene Bmal1”

Science ◽  
2021 ◽  
Vol 372 (6539) ◽  
pp. eabf0922
Author(s):  
Katharine C. Abruzzi ◽  
Cédric Gobet ◽  
Felix Naef ◽  
Michael Rosbash
Keyword(s):  
Circadian Rhythms ◽  
Clock Gene ◽  
Skin Fibroblasts ◽  
Liver Slices ◽  
Free Running

Ray et al. (Reports, 14 February 2020, p. 800) recently claimed temperature-compensated, free-running mRNA oscillations in Bmal1–/– liver slices and skin fibroblasts. We reanalyzed these data and found far fewer reproducible mRNA oscillations in this genotype. We also note errors and potentially inappropriate analyses.

Circadian rhythms in the absence of the clock gene Bmal1

Science ◽  
2020 ◽  
Vol 367 (6479) ◽  
pp. 800-806 ◽  
Author(s):  
Sandipan Ray ◽  
Utham K. Valekunja ◽  
Alessandra Stangherlin ◽  
Steven A. Howell ◽  
Ambrosius P. Snijders ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Circadian Rhythms ◽  
Molecular Clock ◽  
Knockout Mice ◽  
Clock Gene ◽  
Skin Fibroblasts ◽  
Temperature Cycles ◽  
Ets Family

Circadian (~24 hour) clocks have a fundamental role in regulating daily physiology. The transcription factor BMAL1 is a principal driver of a molecular clock in mammals. Bmal1 deletion abolishes 24-hour activity patterning, one measure of clock output. We determined whether Bmal1 function is necessary for daily molecular oscillations in skin fibroblasts and liver slices. Unexpectedly, in Bmal1 knockout mice, both tissues exhibited 24-hour oscillations of the transcriptome, proteome, and phosphoproteome over 2 to 3 days in the absence of any exogenous drivers such as daily light or temperature cycles. This demonstrates a competent 24-hour molecular pacemaker in Bmal1 knockouts. We suggest that such oscillations might be underpinned by transcriptional regulation by the recruitment of ETS family transcription factors, and nontranscriptionally by co-opting redox oscillations.

scholarly journals Response to Comment on “Circadian rhythms in the absence of the clock gene Bmal1”

Science ◽  
2021 ◽  
Vol 372 (6539) ◽  
pp. eabf1941
Author(s):  
Sandipan Ray ◽  
Utham K. Valekunja ◽  
Alessandra Stangherlin ◽  
Steven A. Howell ◽  
Ambrosius P. Snijders ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Clock Gene ◽  
Statistical Significance ◽  
Statistical Measures ◽  
Statistical Algorithm ◽  
Low Amplitude ◽  
Lines Of Evidence

Abruzzi et al. argue that transcriptome oscillations found in our study in the absence of Bmal1 are of low amplitude, statistical significance, and consistency. However, their conclusions rely solely on a different statistical algorithm than we used. We provide statistical measures and additional analyses showing that our original analyses and observations are accurate. Further, we highlight independent lines of evidence indicating Bmal1-independent 24-hour molecular oscillations.

scholarly journals Shared Components of the FRQ-Less Oscillator and TOR Pathway Maintain Rhythmicity in Neurospora

2021 ◽  
pp. 074873042199994
Author(s):  
Rosa Eskandari ◽  
Lalanthi Ratnayake ◽  
Patricia L. Lakin-Thomas
Keyword(s):  
Circadian Rhythms ◽  
Clock Genes ◽  
Nutrient Sensing ◽  
Mass Spectrometry Analysis ◽  
Growth Responses ◽  
Tor Pathway ◽  
Spectrometry Analysis ◽  
Binding Partner ◽  
Binding Partners ◽  
Free Running

Molecular models for the endogenous oscillators that drive circadian rhythms in eukaryotes center on rhythmic transcription/translation of a small number of “clock genes.” Although substantial evidence supports the concept that negative and positive transcription/translation feedback loops (TTFLs) are responsible for regulating the expression of these clock genes, certain rhythms in the filamentous fungus Neurospora crassa continue even when clock genes ( frq, wc-1, and wc-2) are not rhythmically expressed. Identification of the rhythmic processes operating outside of the TTFL has been a major unresolved area in circadian biology. Our lab previously identified a mutation ( vta) that abolishes FRQ-less rhythmicity of the conidiation rhythm and also affects rhythmicity when FRQ is functional. Further studies identified the vta gene product as a component of the TOR (Target of Rapamycin) nutrient-sensing pathway that is conserved in eukaryotes. We now report the discovery of TOR pathway components including GTR2 (homologous to the yeast protein Gtr2, and RAG C/D in mammals) as binding partners of VTA through co-immunoprecipitation (IP) and mass spectrometry analysis using a VTA-FLAG strain. Reciprocal IP with GTR2-FLAG found VTA as a binding partner. A Δ gtr2 strain was deficient in growth responses to amino acids. Free-running conidiation rhythms in a FRQ-less strain were abolished in Δ gtr2. Entrainment of a FRQ-less strain to cycles of heat pulses demonstrated that Δ gtr2 is defective in entrainment. In all of these assays, Δ gtr2 is similar to Δ vta. In addition, expression of GTR2 protein was found to be rhythmic across two circadian cycles, and functional VTA was required for GTR2 rhythmicity. FRQ protein exhibited the expected rhythm in the presence of GTR2 but the rhythmic level of FRQ dampened in the absence of GTR2. These results establish association of VTA with GTR2, and their role in maintaining functional circadian rhythms through the TOR pathway.

scholarly journals Comment on “Circadian rhythms in the absence of the clock gene Bmal1”

Science ◽  
2021 ◽  
Vol 372 (6539) ◽  
pp. eabe9230 ◽  
Author(s):  
Elan Ness-Cohn ◽  
Ravi Allada ◽  
Rosemary Braun
Keyword(s):  
Circadian Rhythms ◽  
Clock Gene ◽  
Insufficient Evidence ◽  
The Core ◽  
Clock Component ◽  
Mouse Tissues ◽  
Associated Data

Ray et al. (Reports, 14 February 2020, p. 800) report apparent transcriptional circadian rhythms in mouse tissues lacking the core clock component BMAL1. To better understand these surprising results, we reanalyzed the associated data. We were unable to reproduce the original findings, nor could we identify reliably cycling genes. We conclude that there is insufficient evidence to support circadian transcriptional rhythms in the absence of Bmal1.

Restricted food access and light-dark: impact of conflicting zeitgebers on circadian rhythms of the rabbit

1993 ◽  
Vol 264 (4) ◽  
pp. R708-R715 ◽  
Author(s):  
B. Jilge ◽  
H. Stahle
Keyword(s):  
Circadian Rhythms ◽  
Phase Difference ◽  
Food Access ◽  
Activity Rhythm ◽  
Light Period ◽  
The Other ◽  
Behavioral Rhythms ◽  
Activity Component ◽  
Common Control ◽  
Free Running

Free-running circadian rhythms of rabbits were exposed to a 11:55-11:55-h light-dark (LD) schedule. After complete entrainment (63 +/- 22 days), the predominantly nocturnally active rabbits were exposed to an additional zeitgeber, restricted food access (RF), which was imposed during the light period. In five animals RF had the same period (T) as the LD cycle (23:50 h), and in five other animals TRF was 24:10 h. At a period of 23:50 h for both zeitgebers, the rhythms of four animals were stably entrained to RF, while in one animal a component of the rhythm broke away from RF and entrained to the LD zeitgeber. In animals exposed to zeitgebers of different periods most of the activity rhythm also entrained to RF, but 20 +/- 7% of the activity entrained to the LD zeitgeber. The light-entrained activity component merged with the RF component when the zeitgebers crossed, and decomposition occurred when the phase difference exceeded 4-6 h. The results indicate that two circadian oscillator systems exist in the rabbit, one entrained by light-dark cycles and the other by feeding-fasting cycles. Both exert common control over a number of overt behavioral rhythms.

RNA Interference of the Clock Gene period Disrupts Circadian Rhythms in the Cricket Gryllus bimaculatus

2008 ◽  
Vol 23 (4) ◽  
pp. 308-318 ◽  
Author(s):  
Yoshiyuki Moriyama ◽  
Tomoaki Sakamoto ◽  
Svetlana G. Karpova ◽  
Akira Matsumoto ◽  
Sumihare Noji ◽  
...  
Keyword(s):  
Rna Interference ◽  
Circadian Rhythms ◽  
Clock Gene ◽  
Gryllus Bimaculatus

scholarly journals The Cell Division Cycle of Euglena gracilis Indicates That the Level of Circadian Plasticity to the External Light Regime Changes in Prolonged-Stationary Cultures

Plants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1475
Author(s):  
Shota Kato ◽  
Hong Gil Nam
Keyword(s):  
Cell Division ◽  
Circadian Rhythms ◽  
Euglena Gracilis ◽  
Cell Cycle Progression ◽  
Light Signal ◽  
Cell Division Cycle ◽  
Regime Changes ◽  
Fitness Advantage ◽  
Subjective Night ◽  
Free Running

In unicellular photosynthetic organisms, circadian rhythm is tightly linked to gating of cell cycle progression, and is entrained by light signal. As several organisms obtain a fitness advantage when the external light/dark cycle matches their endogenous period, and aging alters circadian rhythms, senescence phenotypes of the microalga Euglena gracilis of different culture ages were characterized with respect to the cell division cycle. We report here the effects of prolonged-stationary-phase conditions on the cell division cycles of E. gracilis under non-24-h light/dark cycles (T-cycles). Under T-cycles, cells established from 1-month-old and 2-month-old cultures produced lower cell concentrations after cultivation in the fresh medium than cells from 1-week-old culture. This decrease was not due to higher concentrations of dead cells in the populations, suggesting that cells of different culture ages differ in their capacity for cell division. Cells from 1-week-old cultures had a shorter circadian period of their cell division cycle under shortened T-cycles than aged cells. When algae were transferred to free-running conditions after entrainment to shortened T-cycles, the young cells showed the peak growth rate at a time corresponding to the first subjective night, but the aged cells did not. This suggests that circadian rhythms are more plastic in younger E. gracilis cells.

Abstract P466: Circadian Rhythm Disruptions in a Novel Diabetic db/db-mPer2 Luc Mouse Model

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Tianfei Hou ◽  
Wen Su ◽  
Ming C Gong ◽  
Zhenheng Guo
Keyword(s):  
Blood Pressure ◽  
Circadian Rhythms ◽  
Real Time ◽  
Clock Gene ◽  
Ex Vivo ◽  
Phase Advance ◽  
Luciferase Reporter ◽  
High Time Resolution ◽  
Peripheral Tissues

Db/db mouse, which lacks functional leptin receptor, is an extensively used model of obesity and type 2 diabetes. We and others have demonstrated that db/db mouse has disruptions in circadian rhythms of behavior, physiology and some clock genes. However, systemic investigations of the alterations in clock gene oscillations in multiple systems with high time resolution in this model are impeded by the impractical demand for large number of animals. To overcome this limitation, we cross bred the db/db mouse with mPer2 Luc mouse in which the clock gene Period2 is fused with a luciferase reporter thus allow real-time monitoring of the clock gene Per2 oscillations. The generated db/db-mPer2 Luc mice had the typical diabetic mellitus including obesity, hyperglycemia, hyperinsulinemia, glucose intolerance and insulin resistance. In addition, the db/db-mPer2 Luc mice also exhibited disruptions in circadian rhythms in behavior (locomotor activity), physiology (blood pressure) and metabolism (respiratory exchange ratio and energy expenditure). Using the LumiCycle system, we monitored in real-time of the Per2 oscillations in both the SCN central clock and multiple peripheral tissues ex vivo . The results showed no difference in the phase of the central SCN Per2 oscillation. However, the peripheral tissues that related to metabolism, such as liver and white adipose clocks, displayed 3.28±0.86 and 4.64±1.06 hours of phase advance respectively. Aorta, mesentery artery and kidney, organs play important role in blood pressure homeostasis, showed 0.99±0.37, and 2.12±0.4, and 2.21±0.5 hours phase advance respectively. Interestingly, no difference was observed in the lung and adrenal gland. We then investigated the Per2 oscillation in vivo by using the IVIS imaging system. Consistent with the ex vivo results, the liver Per2 oscillation were phase advanced in vivo. Our findings demonstrated that clock gene Per2 oscillations were disrupted in multiple peripheral tissues but not in central SCN. Moreover, the extent of phase advance in peripheral tissue varies largely. Our results suggest dyssynchrony of the clock oscillations among various peripheral systems likely contribute to the multiple disruptions in physiology and metabolism in diabetic db/db mice.

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