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          Liu Depei's group found that endogenous H2O2 recent rhythmic oscillations regulate the biological clock. Results published in Nature Cell Biology

          On November 26, 2019, Beijing time, Liu Depei's team from the Department of Biochemistry and Molecular Biology / State Key Laboratory of Medical Molecular Biology published a long article entitled " Diurnal oscillations " in Nature Cell Biology . of endogenous H 2 O 2 sustained by p66 Shc regulate circadian clocks ”, for the first time revealed the redox signal changes in a recent rhythm cycle (24 hours), found the redox signal rhythm and classic biological rhythm transcription The key point of direct coupling between negative feedback regulation mechanisms in translation proves the important physiological role of redox signal rhythms in biological rhythms.



          As we all know, almost all life activities have the phenomenon of biological rhythm oscillation. There are currently two theories behind the mechanism. One is the transcription feedback negative feedback loop (TTFL) based on gene transcription, which has been recognized by the Nobel Prize. The other is TTFL. It is the metabolism-based redox oscillators whose mechanism is unclear. Whether or not there is a direct connection between the two mechanisms has been explored and discussed in the field for a long time.


          The research group measured the levels of hydrogen peroxide (H 2 O 2 ) in individual cells and mouse livers at different time points, and found that the H 2 O 2 levels showed a recent rhythmic oscillation. Using a clever screening strategy, the team found that the core biological rhythm regulating molecule CLOCK protein can directly sense the endogenous H 2 O 2 oscillation. Construction of point-mutated mice proved that the cysteine 195 site can be directly oxidatively modified by endogenous H 2 O 2 , and this modification is indispensable for normal biological rhythms. The team also proved that the p66 Shc protein, a downstream molecule of SIRT1 in the apparently modified enzyme SIRTUIN family previously discovered by the laboratory research, is a key factor for endogenous H 2 O 2 rhythmic oscillations, and knocking out this key factor can disrupt endogenous The H 2 O 2 rhythm disrupts the normal oscillatory rhythm and biological clock function of CLOCK redox modification, which eventually leads to the remodeling of the mouse liver transcriptome oscillation, increases the length of the free cycle in the mouse, and influences the light to readjust the rhythm behavior of the mouse. For the first time, this study has truly bridged the gap between the two academic views of the transcription-independent redox oscillation rhythm and the transcription-dependent transcription and translation negative feedback loop (TTFL) mechanism, greatly increasing people ’s ability to drive biological rhythm oscillations. Understanding of fundamental mechanisms.



          In view of the significance of the research work, Professor Ueli Schibler of the University of Geneva, Switzerland, commented on the same period of Nature Cell Biology and highly evaluated the work, saying that the work "actually help in resolving the question of whether TTFL-independent redox oscillators exist in mammalian cells" "And thought" WT CLOCK–BMAL1, but not CLOCKC195S– BMAL1, should rhythmically activate its target genes even in the absence of CRY and PER proteins. " (Comment link: http://www.nature.com/articles/s41556-019-0430-2 )



          Depei Liu's research group Pei Jianfei (third from the right) in 2011, Li Xunkai (first from the left) and 2016 postgraduate Li Wenqi (second from the left) are the first authors. Second right) is the co-corresponding author. The collaborators of this research are the former Cao Jimin Research Group of the Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (now Shanxi Medical University), the Zhang Erquan Research Group of the Beijing Institute of Life Sciences, the Yang Jing researcher of the National Protein Science Center, and the Kate S of Scripps Researcher Carroll. This research obtained the innovation projects of the Chinese Academy of Medical Sciences (CIFMS2017-I2M-1-008, 2016-I2M-1-015 and 2016-I2M-1-011), basic scientific research business fees (2019-RC-HL-006), national nature The scientific foundation (nos. 91849207, 81701387, 91639304, 31471126 and 31571193), the Chinese Academy of Medical Sciences' Medical Epigenetics Research Center (2017PT31035 and 2018PT31015), the special post-doctoral research fund (2017T100051), and the youth talent award. ) (Article link: http://www.nature.com/articles/s41556-019-0420-4 )