Bokai Zhu, Ph.D. | Cell Molecular and Systems Biology PhD Program

Possible Rotation Projects:

Interrogate principles of nuclear speckle organization of genome
Nuclear speckle rejuvenation to alleviate proteinopathy and aging-related diseases
Mapping and engineering nuclear speckle dynamics to decode and reprogram aging and neurodegeneration

Training Technologies Used:

Genome-wide sequencing
Live-cell imaging
Biomolecular condensate biology
CRISPR genome engineering
Quantitative computational analysis.

Education & Training

Ph.D.-Molecular Medicine Program, Penn State University, University Park, PA, 2012
B.S.-Biology, Peking University, China, 2006
Post-doctoral training, Baylor College of Medicine, 2017

Recent Publications

Dion, W^#., Tao, Y^#., Chambers, M., Zhao, S., Arbuckle, R., Sun, M., Kubra, S., Schaich, M., Nie, Y., Ye, M., Jamal, I., Larsen, M.B., Camarco, D., Dupont, C., Wang, H., Wang, B., Liu, S., Pi, S., Van Houten, B., Chen, B.B., Chen, Y.^*, Chen, X^*., and Zhu, B^*. SON-dependent nuclear speckle rehabilitation alleviates proteinopathies. Nature Communications (2025). DOI: https://doi.org/10.1038/s41467-025-62242-7.

Lv B, Dion, W, Yang, H, Xun, J, Kim D, Zhu, B, and Tan JX. A TBK-independent primordial function of STING in lysosome biogenesis. Molecular Cell (2024). DOI: 10.1016/j.molcel.2024.08.026

Zhu B*, Liu S, David NL, Dion W, Doshi NK, Siegel LB, Amorim T, Andrews RE, Kumar GVN, Li, H, Irfan S, Pesaresi T, Sharma AX, Sun M, Fazeli PK, and Steinhauser ML *. (* co-corresponding authors). Evidence for ~12-h ultradian gene program in humans. npj Biological Timing and Sleep (2024). DOI: 10.1038/s44323-024-00005-1.

Scott, MR, Zong W, Ketchesin KD, Seney ML, Tseng, GC, Zhu, B*, McClung CA*. (* co-corresponding authors). Twelve-hour rhythms in transcript expression within the human dorsolateral prefrontal cortex are altered in schizophrenia. PLoS Biology (2023). DOI: https://doi.org/10.1371/journal.pbio.3001688

Dion, W., Ballance, H., Lee J., Pan Y., Irfan S., Edwards, C., Sun., M., Zhang J., Zhang X., Liu S. and Zhu, B. Four-dimensional nuclear speckle phase separation dynamics regulate proteostasis. Science Advances (2022); DOI: 10.1126/sciadv.abl4150

Meng, H, Gonzalez, N, Lonard, D, Putluri N, Zhu, B, Dacso, CC, York, B and O'Malley BW. XBP1 links the 12-hour clock to NAFLD and regulation of membrane fluidity and lipid homeostasis. Nature Communications (2020); DOI: https://doi.org/10.1038/s41467-020-20028-z

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 Biology (2020); DOI: 10.1371/journal.pbio.3000580

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

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

Full List of Publications

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Research Interests

Proteins are the building blocks of life, but keeping them healthy is a constant challenge for cells. The system that manages protein folding, repair, and clearance—known as proteostasis—gradually declines with age and is a major contributor to neurodegenerative diseases such as Alzheimer's disease and related dementias. In our laboratory, we discovered that proteostasis is not maintained at a constant level but instead follows a previously unrecognized 12-hour biological rhythm, governed by a molecular clock that is distinct from the familiar 24-hour circadian clock. This mammalian 12-hour oscillator enables cells to anticipate recurring periods of stress and proactively maintain protein homeostasis. More recently, we have uncovered a central role for nuclear speckles—dynamic, liquid-like compartments within the nucleus—in regulating this process. We found that nuclear speckles function as protein quality-control hubs that sense cellular stress, organize gene expression programs that maintain proteostasis, and can be rejuvenated to restore cellular function. By resetting these structures, we have improved proteostasis and reduced toxic protein accumulation in experimental models of tauopathy, a devastating neurodegenerative disorder.

Our research integrates cell biology, biochemistry, genomics, biophysics, mouse physiology, and computational biology to uncover fundamental principles of cellular organization and translate these discoveries into new therapeutic strategies for aging and neurodegenerative diseases. Graduate students in the lab receive interdisciplinary training in cutting-edge approaches, including genome-wide sequencing, live-cell imaging, biomolecular condensate biology, CRISPR genome engineering, and quantitative computational analysis, while pursuing projects at the interface of basic biology and disease.