Proteostasis, the cellular mechanism that governs the synthesis, folding, and degradation of proteins, is crucial for maintaining proteome integrity, especially under proteotoxic stress. A decline in protein quality control is closely linked to aging and neurodegenerative diseases.
Traditionally, proteostasis was believed to be constant under basal conditions. However, using novel mathematical tools, our lab has uncovered a surprising 12-hour rhythm in global proteostasis dynamics in normal cells, operating under physiological conditions. This 12-hour rhythm is regulated by a cell-autonomous mammalian 12-hour ultradian oscillator, independent of the 24-hour circadian clock and the cell cycle. Our lab is interested in studying the gene regulatory network, chromatin and epigenetic landscape, biological function, and evolutionary origin of the 12-hour oscillator. We are further pursuing a new direction following our recent discovery of the critical role of nuclear speckle liquid-liquid phase separation in controlling proteostasis.
We are actively studying how nuclear speckle sense proteostasis stress and preemptively elicit stress response. Lastly, we are developing innovative strategies for rejuvenating nuclear speckles to combat protein misfolding diseases, such as tauopathy in neurodegeneration.
Potential rotation projects:
1) Developing 12h-clock reporter system using CRISPR-CAS9 based imaging approaches.
2) Identifying non-cell autonomous regulators of 12h clock and protein quality control using innovative proximity- labeling biochemical approaches.
3) Identify epigenetic regulators of mammalian 12h clock and UPR.
4) 12h clock in senescence and aging.
5) 12h clock in humans.
6) Nuclear speckle rejuvenation in combating proteinopathies.