E. Erquan Zhang, Ph.D.

Associate Investigator, NIBS, Beijing，China

Phone：010-80726688-8605

Fax： 010-80727512

E-mail：zhangerquan@nibs.ac.cn

Education

Professional Experience

Research Description

We have spent the past many years in exploring a broad range of circadian rhythms in mammals. Having now made some substantial discoveries and thereby clarified our future scientific goals, we are now able to narrow down to focus on specific projects for the next phase of the lab at NIBS.

1. An "A" impact of the circadian clock: Adenosine/ATP/ATPase

Our chemical screen identified an adenosine-analog (cordycepin) that may regulate the circadian phase, and demonstrated that its physiological metabolite’s target was a novel clock component RUVBL2, an AAA-type ATPase that functions as a hub of the gigantic super-complex responsible for circadian transcription. Interestingly, we have observed a cross-species, or even trans-kingdom, effect of the clock regulation by cordycepin (or its derivatives), suggesting that an evolutionarily conserved mechanism may be hidden within the phenomena we regularly examine in the lab. Generally, it is believed that the clock mechanism consists of a negative transcriptional/translational feedback loop (TTFL) which possesses a similar architecture but which comprises distinct components in various organisms. However, the administration of cordycepin in other species, including the model plant species Arabidopsis thaliana, also shift the clock phase; thus RUVBL2 may be one of only a few conserved components sitting within the transcriptional regulatory mega-complex.

2. The function and regulation of the brain clock in sleep deprivation

Disruption of sleep is widely believed to have impacts on the brain clock. For instance, people frequently complain that their mental clocks are disturbed once they experience even just a mild instance of sleep loss. Indeed, a few hormonal oscillations (such as hGH and T3/T4) are dampened after a 6 h sleep loss according to clinical reports. Since our technical development of fiber photometry enables us to monitor the brain clock in live mammals, we utilized it to measure the brain clock in sleep-deprived and sleep-rebound conditions. Unexpectedly (but not particularly surprisingly), we observed only very subtle, if any, perturbations of the circadian oscillation in the suprachiasmatic nucleus (SCN) during sleep deprivation or its aftermath. One explanation for this observation is that there may be some other brain regions which are more susceptible to the sleep perturbation. We are thus interested in understanding where these regions may be located, how sleep loss (and/or recovery) may affect their local clocks, and which biological signals may be involved. These studies may shed light to help understand the basis of sleep, which remains mysterious even after decades of intensive investigations.

3. Circadian translational medicine

We have had a long-time interest in studying human chronobiology. In the new phase of the lab, we plan to collaborate with certain hospitals in China to focus on the human clock. For instance, we have recently identified a dual-mutant PER2 that causes disrupted circadian behaviors from a family-based human genetic study (ongoing project). In addition, it has been reported that elderly people have a weak clock, and our study of mammals implies that Tibetan natives with EPAS1 mutants may also have crippled clock. Therefore, we are currently devising non-invasive methods for monitoring clock dynamics and sleep quality in humans.

Finally, our discovery of a set of compounds that regulate the clock phase and amplitude has proven their therapeutic potentials. We now aim to work with a NIBS spin-off company to pursue the treatment of jet-lag, shift-work, and possibly aging.

All Publications:

https://scholar.google.com/citations?hl=en&user=x1V6G-gAAAAJ

Selected Publications (since 2017):

1. Sang, D.?, Lin, K.?, Yang, Y.?, Ran, G., Li, B., Chen, C., Li, Q., Ma, Y., Lu, L., Cui, X.-Y., Liu, Z., Lv, S.-Q., Luo, M., Liu, Q., Li, Y., and Zhang, E.E.* Prolonged sleep deprivation induces a cytokine storm-like syndrome in mammals. (2023) Cell 186: 5500-5516 {Highlighted by Nature Reviews Immunology: “Sleep deprivation whips up cytokine storm”}

2. Yu, Z. and Zhang, E.E.* Disrupted circadian rhythms in the plateau pika. (2023) Trends in Neurosciences 46: 1005-1007

3. Jiang, W.?*, Jin, L.?, Ju, D.?, Lu, Z.?, Wang, C., Guo, X., Zhao, H., Shen, S., Cheng, Z., Shen, J., Zong, G., Chen, J., Li, K., Yang, L., Zhang, Z., Feng, Y., Shen, J.Z., Zhang, E.E.*, and Wan, R.* The pancreatic clock is a key determinant of pancreatic fibrosis progression and exocrine dysfunction. (2022) Science Translational Medicine 14: eabn3586 {Highlighted by Nature Reviews Gastroenterology & Hepatology: “Stopped clock promotes fibrosis in chronic pancreatitis”}

4. Liu, N.?, Tian, H.?, Yu, Z.?, Zhao, H.?, Li, W.?, Sang, D., Lin, K., Cui, Y., Liao, M., Xu, Z., Chen, C., Guo, Y., Wang, Y., Huang, H-w, Wang, J., Zhang, H., Wu, W., Huang, H., Lv, S., Guo, Z., Wang, W., Zheng, S., Wang, F., Zhang, Y.*, Cai, T.*, and Zhang, E.E.* A highland-adaptation mutation of the Epas1 protein increases its stability and disrupts the circadian clock in the plateau pika. (2022) Cell Reports 39: 110816

5. Ju, D.?, Zhang, W.?, Yan, J., Zhao, H., Li, W., Wang, J., Liao, M., Xu, Z., Wang, Z., Zhou, G., Mei, L., Hou, N., Ying, S., Cai, T., Chen, S., Xie, X., Lai, L., Tang, C., Park, N., Takahashi, J.S., Huang, N., Qi, X.*, and Zhang, E.E.* Chemical Perturbations Reveal That RUVBL2 Regulates the Circadian Phase in Mammals. (2020) Science Translational Medicine 12: eaba0769 {Featured by Editor in the issue: “Shifting clock gears”; and by Nature Reviews Drug Discovery: “Shortening jet-lag recovery”; Highlighted by Faculty of 1000 (Very Good)}

6. Peng, S.?, Xiao, W.?, Ju, D.?, Sun, B., Hou, N., Liu, Q., Wang, Y., Zhao, H., Gao, C., Zhang, S., Cao, R., Li, P., Huang, H., Ma, Y., Wang, Y., Lai, W., Ma, Z., Zhang, W., Huang, S., Wang, H., Zhang, Z., Zhao, L., Cai, T., Zhao, Y., Wang, F., Nie, Y., Zhi, G., Yang, Y.*, Zhang, E.E.*, and Huang, N.* Identification of Entacapone as a Chemical Inhibitor of FTO Mediating Metabolic Regulation Through FOXO1. (2019) Science Translational Medicine 11: eaau7116 {Featured by Editor in the issue: “The skinny on FTO”}

7. Mei, L., Fan, Y., Lv, X., Welsh, D.K., Zhan, C.*, and Zhang, E.E.* Long-term in vivo Recording of Circadian Rhythms in Brains of Freely Moving Mice. (2018) Proceedings of the National Academy of Sciences U.S.A. 115: 4276-4281 {Highlighted by Faculty of 1000 (Very Good)}

8. Wu, Y.?, Tang, D.?, Liu, N., Xiong, W., Huang, H., Li, Y., Ma, Z., Zhao, H., Chen, P., Qi, X., and Zhang, E.E.* Reciprocal Regulation between the Circadian Clock and Hypoxia Signaling at the Genome Level in Mammals. (2017) Cell Metabolism 25: 73-85 {Cover story of the issue; Featured by Science Signaling, “Daily oxygen rhythms”}

Awarded Patents (since 2017):

1. Zhang, E., Qi, X., Ju, D., Zhou, G., Zhao, H., Mei, L., Wang, Z., and Liang, L. Nucleoside analogue regulating mammalian circadian rhythm. WIPO Publication # WO2018133835A1 (granted in China and Japan; pending in USA, European Union, etc; PCT priority date: 02.02.2017)

2. Zhang, E., Zhan, C., and Mei, L. A method and instrumental design for long-term and real-time recording of gene transcriptions in live animals. NIPA Application# 2017101661043 (granted in China)

Invited Talks (since 2017):

1. Society for Research on Biological Rhythms Biennial Meeting, Amelia Island, Florida, USA, May 2022 (Session Chair)

2. NeuroZoom Research Talks, Virtual Conference, China, October 2020

3. Society for Research on Biological Rhythms Biennial Meeting, Virtual Conference, USA, June 2020

4. Center for Circadian Biology Annual Meeting, University of California San Diego, USA, March 2020

5. Keystone Symposia on "Hypoxia: Molecules, Mechanisms and Disease", Keystone, Colorado, USA, January 2020 (Session Chair)

6. XVI Congress, European Biological Rhythm Society, Lyon, France, August 2019

7. Sapporo Symposium on Biological Rhythms, Japanese Society for Chronobiology, Sapporo, Japan, July 2018

8. ITbM Research Seminar, Nagoya University, Japan, July 2018

9. Society for Research on Biological Rhythms Biennial Meeting, Amelia Island, Florida, USA, May 2018

10. Gordon Research Conference on Chronobiology, Stowe, Vermont, USA, July 2017