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:

1. 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

2. 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

3. 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)}

4. Han, K.*, Mei, L.*, Zhong, R., Pang, Y., Zhang, E.E.†, and Huang Y.† A Microfluidic Approach for Experimentally Modeling the Intercellular Coupling System of a Mammalian Circadian Clock at Single-cell Level. (2020) Lab on a Chip 20, 1204-1211

5. 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”}

6. 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); Detailed protocol can be viewed in a video publication of JOVE 56765}

7. 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” (Editors' Choice)}

8. Zhang, E.E.* and Kay, S.A.† Clocks Not Winding Down: Unraveling Circadian Networks. (2010) Nature Reviews Molecular Cell Biology 11: 764-776 {Invited Review, 10-year Anniversary Series}

9. Zhang, E.E.*, Liu, Y.*, Dentin, R., Pongsawakul, P.Y., Liu, A.C., Hirota, T., Nusinow, D.A., Sun, X., Landais, S., Kodama, Y., Brenner, D., Montminy, M.† and Kay, S.A.† Cryptochrome Mediates Circadian Regulation of cAMP Signaling and Hepatic Gluconeogenesis. (2010) Nature Medicine 16: 1152-1156 {Featured by Nature Medicine, “High glucose, no cry” (News and Views); Highlighted by Faculty of 1000 (Very Good)}

10. Zhang, E.E.*, Liu, A.C.*, Hirota, T.*, Miraglia, L.J., Welch, G., Pongsawakul, P.Y., Liu, X., Atwood, A., Huss, J.W.III., Janes, J., Su, A.I., Hogenesch, J.B.†, and Kay, S.A.† A Genome-wide siRNA Screen for Modifiers of the Circadian Clock in Human Cells. (2009) Cell 139: 199-210 {Highlighted by Faculty of 1000 (Exceptional)}

Patent Applications:

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

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

Invited Conference Talks:

1. Society for Research on Biological Rhythms Biennial Meeting, Virtual Conference, May 30- June 3, 2020

2. 10^th Annual Symposium of Center for Circadian Biology, University of California San Diego, La Jolla, California, USA, March 4-6, 2020

3. Keystone Symposia on "Hypoxia: Molecules, Mechanisms and Disease", Keystone, Colorado, USA, January 18-24, 2020 (Session Chair)

4. XVI Congress, European Biological Rhythm Society, Lyon, France, August 25-30, 2019

5. Sapporo Symposium on Biological Rhythms, Japanese Society for Chronobiology, Sapporo, Japan, July 11-16, 2018

6. Society for Research on Biological Rhythms Biennial Meeting, Amelia Island, Florida, USA, May 12-16, 2018

7. Gordon Research Conference on Chronobiology, Stowe, Vermont, USA, July 16-21, 2017

8. Cold Spring Harbor Asia Meeting on Biological Rhythms, Suzhou, China, October 26-30, 2015 (Session Chair)

Organized Conferences:

1. Organizing Committee: 5^th World Congress of Chronobiology (WCC), Suzhou, China, April 25-28, 2019

2. Co-organizer of two (with Dr. Qinghua Liu): 1^st Beijing Symposium on the Circadian Clock and Sleep Research, Beijing, China, April 23-24, 2019

3. Co-organizer of two (with Dr. Jinhu Guo): Satellite symposium on "Biological Rhythms: Health & Adaptation", Chinese Society for Cell Biology Annual Meeting, Nanjing, China, April 11-12, 2018

4. Organizing Committee: 2^nd Asian Forum on Chronobiology (AFC), Hohhot, Inner Mongolia, China, June 25-27, 2017

5. Co-organizer of three (with Drs. Ying Xu and Yi Rao): International ChronoBiology Summer School(CBS), Beijing, China, August 1-6, 2016

Other Academic Activities:

1. Ad Hoc Reviewer for Scientific Journals: Science, Nature Reviews Drug Discovery, Cell Metabolism, Journal of Clinical Investigation, PLoS Biology, Cell Research, PNAS, iScience, Journal of Biological Rhythms, Scientific Reports, Trends in Endocrinology and Metabolism, Frontiers in Molecular Neuroscience / Pharmacology / Physiology, Brian Science Advances,etc.

2. Ad Hoc Reviewer for Research Funding Agencies: National Natural Science Foundation of China(NSFC), Ministry of Science and Technology (MOST) of China, Agence Nationale de la Recherche(ANR) of France

3. Associate Editor: Frontiers in Molecular Neuroscience

4. Guest Associate Editor: Frontiers in Pharmacology

5. Founding Vice President (since 2015): Chinese Society for Biological Rhythms (CSBR)