Science contention | The core position of the biological clock "conductor" BMAL1 gene shakes?

Written | Edited by Qi | Enzyme Beauty's life is inevitable.
Such experiences are inevitable.
For example, night shifts need to be taken off, jet lag is needed to go abroad, otherwise the body will be overwhelmed.

In fact, this is all the biological clock "in the dark".

Circadian clocks, as an almost ubiquitous feature in eukaryotic life, are a hot topic of research and discussion by scientists (see "Collector's Edition" Science Review | Current Status and Prospects of Circadian Clocks, Cancer and Chemotherapy-Systematic Reviewing the Impact of Biological Clock Disturbance on Human Health), it is generally accepted in this field that the biological clock is composed of transcriptional-translational feedback loops (TTFLs) at the molecular level, and TTFLs drive the periodicity of clock-related gene products.
expression.

Among them, BMAL1 (also known as MOP3 or ARNTL) is considered an indispensable component, as a transcription factor forming a heterodimer with CLOCK to jointly activate circadian gene expression.

Many studies have shown that the destruction of Bmal1 in mammals can lead to a series of physiological abnormalities, including the disappearance of circadian rhythm behavior, sleep-wake cycle disorders, abnormal retinal function, neurodegeneration, and shortened lifespan, while deletion of Bmal1 gene will disrupt the core Periodic oscillation of clock components.

However, some studies have suggested that Bmal1 may not be necessary for all molecular oscillations outside the standard circadian circuit, especially at the genome-wide or proteome level; in addition, the classic TTFL model does not seem to be a comprehensive representation of the biological clock regulation of all molecules.
the way.So is the position of Bmal1 in the regulation of the circadian rhythm of the molecule still "unshakable"? On February 14, 2020, the Akhilesh B.
Reddy team from the University of Pennsylvania, USA, published an article titled Circadian rhythms in the absence of the clock gene Bmal1 in Science.
This study found that Bmal1 knockout mice In the case of skin fibroblasts and liver slice tissues without any external driving factors (such as daily light or temperature cycles), their transcriptome, proteome and phosphorylated proteome can all show 24h oscillations, Bmal1 It does not seem to be a necessary regulator to control the body's circadian rhythm.
There may be other driving factors for the biological clock.

After the article was published, related fields made inconsistent voices about the experimental results and experimental conclusions of the research.

In this regard, the team (hereinafter referred to as Ray et al.
) published a revised version of the errata on January 29, 2021, and the conclusion still supports the original view.

On April 16, 2021, the Rosemary Braun team from Northwestern University (hereinafter referred to as Ness-Cohn, etc.
) made a comment on the research of Ray et al.

Ness-Cohn et al.
re-analyzed the data of Ray et al.
's three experiments (identification of periodic genes; temperature compensation studies; AM/PM phase shift experiments) according to the given method.
The various genes detected as having cycle rhythms may be false positives or experimental artifacts, and false cycles may also be caused by the environment or the interaction between cells.

Finally, Ness-Cohn et al.
believe that although the possibility of Bmal1–/– may have circadian dynamics cannot be ruled out, this study failed to find any evidence of consistent observation of circadian rhythms.

In addition, Michael Rosbash from Brandeis University in the United States and Felix Naef of the Swiss Federal Institute of Technology in Lausanne (hereinafter referred to as Abruzzi, etc.
) also questioned this research in the Science magazine at the same time.Abruzzi et al.
also believe that there are experimental artifacts in the study.
For example, the oscillations of Bmal1–/– liver slices are generally low in amplitude, and mouse skin fibroblast data also show similar trends.
These are most likely to be experimental artifacts.
Sources, therefore, these data still do not support the existence of "Bmal1-independent cellular endogenous molecular oscillators.
"
Abruzzi et al.
also found a surprising phenomenon in the study of Ray et al.
Most other clock gene transcripts did not show any rhythm in wild-type mice, but they showed a 24-hour rhythm in Bmal1–/– Fluctuations and lack of rhythm in wild-type samples also suggest that the liver experiment is technically flawed.

In addition to the above points, Abruzzi et al.
also re-analyzed several other experimental data and still refuted the existence of the "cell autonomous oscillator independent of Bmal1" proposed by Ray et al.

In response to the doubts of Ness-Cohn et al.
and Abruzzi et al.
, Ray et al.
also responded one by one in the same magazine.

Ray et al.
proposed that there are more than 2000 rhythm transcripts in the AM and PM data sets in Bmal1 knockout.
Such a large number of rhythm records is unlikely to be attributed to the "noise" considered by Ness-Cohn et al.
; the skin fibroblasts described in the study are diurnal Rhythmic transcriptome experiments are not completed at the same time, but are conducted across different stages of the paper preparation and revision process in a 2-3 year time frame, which can explain some inconsistencies in the results.

Ray et al.
proposed that if the research results are considered to be caused by “noise” instead of real existence, Ness-Cohn et al.
can repeat the experiment in an environment where they believe that there is no external influence at all to verify the Bmal1–/– cells cultured under constant conditions There is absolutely no 24-hour molecular oscillation. In another response, Ray et al.
believed that Abruzzi et al.
used the JTK algorithm for repeated analysis, instead of the RAIN algorithm they used, and did not compare the results of the two methods.
According to the "Biorhythm Genome Scale Analysis Guide" JTK It is not the "gold standard" in this field, so Abruzzi and others have no reason to believe that the JTK algorithm is superior to RAIN.
After reanalyzing the JTK algorithm, it can be found that the FDR in JTK is more conservative than the real FDR, that is, JTK will underestimate the rhythm transcript.
.

In addition, in response to the "surprising phenomenon" proposed by Abruzzi et al.
, Ray et al.
once again emphasized the rigor of the experimental conditions, and the results were not accidental.

In addition to this study by Ray et al.
, Welz et al.
used different Bmal1 gene knockout models to find the circadian rhythm of the skin [1].

882 transcripts of these data overlap between the skin fibroblast data of Ray et al.
and the in vivo epidermis data.

In addition, there is also evidence that Bmal1–/– skin fibroblasts exhibit diurnal metabolic flow oscillations under constant conditions [2].

These data also provide further evidence for the self-sustaining circadian rhythm oscillations of Bmal1–/– cells and tissues under constant conditions.

So is the Bmal1 gene still serving as a core factor in molecular circadian regulation? Or are there other drivers? Further, more in-depth research is needed.

Original link: 1.
https://science.
sciencemag.
org/lookup/doi/10.
1126/science.
abe92302.
https://science.
sciencemag.
org/lookup/doi/10.
1126/science.
abf09223.
https://science .
sciencemag.
org/lookup/doi/10.
1126/science.
abf19304.
https://science.
sciencemag.
org/lookup/doi/10.
1126/science.
abf1941 Platemaker: Eleven References 1.
P.
-S.
Welz, VM Zinna, A.
Symeonidi, KB Koronowski, K.
Kinouchi, JG Smith, IM Guillén, A.
Castellanos, S.
Furrow, F.
Aragón, G.
Crainiciuc, N.
Prats, JM Caballero, A.
Hidalgo, P.
Sassone -Corsi, SA Benitah, BMAL1-Driven Tissue Clocks Respond Independently to Light to Maintain Homeostasis.
Cell 177, 1436– 1447.
e12 (2019).
doi:10.
1016/j.
cell.
2019.
05.
009 Medline2.
R.
Ch, G.
Rey, S.
Ray, PK Jha, PC Driscoll, MS Dos Santos, DM Malik, R.
Lach, AM Weljie, JI MacRae, UK Valekunja, AB Reddy,Rhythmic glucose metabolism regulates the redox circadian clockwork in human red blood cells.
Nat.
Commun.
12, 377 (2021).
doi:10.
1038/s41467-020-20479-4 Instructions for reprinting by Medline【Original article】BioArt original article, personal forwarding is welcome Sharing, reprinting without permission is prohibited, the copyright of all published works is owned by BioArt. BioArt reserves all statutory rights and offenders must be investigated.