Bokai Zhu, Ph.D.

  • Assistant Professor
  • Department of Medicine
  • Division of Endocrinology and Metabolism, Aging Institute of UPMC

Education & Training

  • Ph.D.-Molecular Medicine Program, Penn State University, University Park, PA, 2012
  • B.S.-Biology, Peking University, China, 2006

Research Interest Summary

12-hour ultradian rhythm of proteostasis, mRNA metabolism, and stress response

Research Categories

Research Interests

Proteostasis governs the synthesis, folding, and degradation of proteins within the cell and is the organism’s principal mechanism of maintaining proteome integrity in response to endoplasmic reticulum stress. Interestingly, contrary to the traditional belief that proteostasis process is constant under basal conditions, we discovered that instead, a 12h rhythm of proteostasis occur in normal cells under physiological conditions. This 12h rhythm of proteostasis dynamics is controlled by a cell-autonomous mammalian 12h oscillator that runs independently from the 24h circadian clock. Dr. Zhu’s lab is currently investigating the regulation as well as the physiological/pathological functions of the 12h-clock, taking a combination of computational, biochemical, genetic, cellular, imaging and genomic approaches. Specific areas of the study are 1) developing sensitive and robust 12h-clock reporter systems using CRISPR-CAS9 based imaging approaches, 2) to determine the transcriptional and post-transcriptional regulatory network of 12h-clock control combining transcriptome, cistrome and epigenome profiling with innovative computational analysis, 3) to determine how the 12h-clock regulates the metabolism dynamics and how cellular metabolism feeds back to influence the 12h rhythms of gene expression through epigenetic and other mechanisms; 4) to identify non-cell autonomous regulators/factors of 12h clock and protein quality control, and 5) to establish the causal relationships between the disruption of a 12h-clock with progression to aging-related metabolic diseases and the aging process as a whole, with the ultimate goal to successfully translate the these knowledge into chronotherapy-based medicine and disease prevention.

Representative Publications

Asher G, Zhu B. Beyond circadian rhythms: emerging roles of ultradian rhythms in control of liver functions. Hepatology. 2022 May 19;. doi: 10.1002/hep.32580. [Epub ahead of print] Review. PubMed PMID: 35591797; PubMed Central PMCID: PMC9674798.

Meng H, Gonzales NM, Jung SY, Lu Y, Putluri N, Zhu B, Dacso CC, Lonard DM, O'Malley BW. Defining the mammalian coactivation of hepatic 12-h clock and lipid metabolism. Cell Rep. 2022 Mar 8;38(10):110491. doi: 10.1016/j.celrep.2022.110491. PubMed PMID: 35263593; PubMed Central PMCID: PMC8958721.

Dion W, Ballance H, Lee J, Pan Y, Irfan S, Edwards C, Sun M, Zhang J, Zhang X, Liu S, Zhu B. Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis. Sci Adv. 2022 Jan 7;8(1):eabl4150. doi: 10.1126/sciadv.abl4150. Epub 2022 Jan 5. PubMed PMID: 34985945; PubMed Central PMCID: PMC8730402.

Meng H, Gonzales NM, Lonard DM, Putluri N, Zhu B, Dacso CC, York B, O'Malley BW. XBP1 links the 12-hour clock to NAFLD and regulation of membrane fluidity and lipid homeostasis. Nat Commun. 2020 Dec 4;11(1):6215. doi: 10.1038/s41467-020-20028-z. PubMed PMID: 33277471; PubMed Central PMCID: PMC7718229.

Pan Y, Ballance H, Meng H, Gonzalez N, Kim SM, Abdurehman L, York B, Chen X, Schnytzer Y, Levy O, Dacso CC, McClung CA, O'Malley BW, Liu S, Zhu B. 12-h clock regulation of genetic information flow by XBP1s. PLoS Biol. 2020 Jan;18(1):e3000580. doi: 10.1371/journal.pbio.3000580. eCollection 2020 Jan. PubMed PMID: 31935211; PubMed Central PMCID: PMC6959563.

Antoulas, A.C., Zhu, B., Zhang, Q., York, B., O'Malley, B.W. and Dacso, C.C. A novel mathematical method for disclosing oscillations in gene transcription: a comparative study. PloS One (2018); 13(9): e0198503

Zhu, B., Dacso, C.C. and O'Malley, B.W. Unveiling “Musica Universalis” of the Cell: A brief history of biological 12h rhythms. Journal of Endocrine Society (2018); 2(7):727-752. DOI: 10.1210/js.2018-00113

Dasgupta, S., Rajapakshe, K., Zhu, B., Nikolai B.C., Yi, P., Putluri, N., Choi, J.M., Jung, S.Y., Coarfa, C., Westbrook, T.F., Zhang, X.H., Foulds, C.E., Tsai, S.Y., Tsai, M.J. and O’Malley, B.W. Glycolytic enzyme PFKFB4 activates oncogenic coactivator SRC-3 to drive breast tumorigenesis and metastasis. Nature (2018). DOI: 10.1038/s41586-018-0018-1

Gates, L.A., Shi, J., Rohira, A.D., Feng, Q., Zhu, B., Bedford, M.T., Sagum, C.A., Jung, S.Y., Qin, J., Tsai, M., Tsai, S.Y., Li, W., Foulds, C.E. and O’Malley, B.W. Acetylation on histone H3 lysine 9 mediates a switch from transcription initiation to elongation. Journal of Biological Chemistry (2017). DOI: 10.1074/jbc.M117.802074 

Zhu, B., Zhang, Q., Pan, Y., Mace, E.M., York, B., Antoulas, A.C., Dacso, C.C. and O'Malley, B.W. A cell-autonomous mammalian 12 hr clock coordinates metabolic and stress rhythms. Cell Metabolism (2017). 25(6):1305-1319.e9. DOI: 10.1016/j.cmet.2017.05.004 [Featured in “editors’ choice” highlight in the issue of Science :30 Jun 2017:]

[Featured in “editors’ choice” highlight in the issue of Science Translational Medicine :28 Jun 2017:]  

[Featured in the Scientist magazine:

Romere, C., Duerrschmid, C., Bournat, J., Constable, P., Jain, M., Xia, F., Saha, P.K., Del Solar, M., Zhu, B., York, B., Sarkar, P., Rendon, D.A., Gaber, M.W., LeMaire, S.A., Coselli, J.S., Milewicz, D.M., Sutton, R., Butte, N.F., Moore, D.D. and Chopra, A.R. Asprosin, a fasting-induced glucogenic protein hormone. Cell (2016). DOI: 10.1016/j.cell.2016.02.063   

Zhu, B., Gates, L.A., Stashi, E., Dagupta, S., Gonzalez, N., Dean, A., Dasco, C.C., York, B. and O’Malley, B.W. Co-activator-dependent oscillation of chromatin accessibility dictates circadian gene amplitude via REV-ERB loading. Molecular Cell (2015) Nov 20. DOI: 10.1016/j.molcel.2015.10.024

Fleet, T., Zheng, B., Lin, F., Zhu, B., Dagupta, S., Stashi, E., Tackett, B., Thevananther, S., Rajapakshe, K., Gonzalez, N., Dean, A., Mao, J., Malonvannaya, A., Qin, J., Coarfa, C., Demayo, F., Dasco, C.C., Foulds, C.E., O’Malley, B.W. and York, B. SRC-2 orchestrates polygenic inputs for fine-tuning glucose homeostasis. Proceedings of the National Academy of Sciences (2015) Oct 20. DOI: 10.1073/pnas.1519073112

Zhu, B., Ferry, C.H., Markell, L.M., Blazanin, N., Glick, A.B., Gonzalez, F.J. and Peters, J.M. The nuclear receptor PPARβ/δ promotes oncogene-induced cellular senescence through repression of endoplasmic reticulum stress. Journal of Biological Chemistry (2014) Jul 18;289(29):20102-19

Stashi, E., Lanz, R.B., Mao, J., Michailidis, G.., Zhu, B., Kettner, N., Putluri, N., Reineke, E.L., Reineke, L.C., Dasgupta, S., Dean, A., Stevenson, C.R., Sivasubramanian, N., Sreekumar, A., DeMayo, F., York, B., Loning, F. and O’Malley, B.W. SRC-2 is an essential co-activator for orchestrating metabolism and circadian rhythm. Cell Reports (2014) 6 (4): 633-645  

Full List of Publications

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