Publication
For a complete list of my published work and preprints, visit https://orcid.org/0000-0003-4538-5728
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Chenshu's Postdoc work (selected)
Liu, C.* and Dernburg, A.F*. (2024) Chemically induced proximity reveals a Piezo-dependent meiotic checkpoint at the oocyte nuclear envelope. Science DOI: https://www.science.org/doi/10.1126/science.adm7969 (Also on bioRxiv. doi: https://doi.org/10.1101/2023.10.28.564506 )
Successful sexual reproduction relies on robust quality control during meiosis. Assembly of the synaptonemal complex between homologous chromosomes (synapsis) regulates meiotic recombination and is crucial for accurate chromosome segregation. Synapsis defects can trigger cell cycle delays and apoptosis. By developing and deploying a new chemically induced proximity system, we identify key players in this quality control pathway in Caenorhabditis elegans. We find that in response to synapsis defects, persistence of the Polo-like kinase PLK-2 at the nuclear envelope phosphorylates and destabilizes the nuclear lamina and triggers oocyte apoptosis. Unexpectedly, we find that a mechanosensitive Piezo1/PEZO-1 channel localizes to the nuclear envelope and is required to transduce this signal to promote apoptosis. This is the first evidence of a mechanosensitive ion channel in detecting and responding to nuclear events. The chemically induced proximity system we developed will enable many new research directions in C. elegans and other organisms.
Liu, C.*, Rex, R., Lung, Z., Wang, J.S., Wu, F., Kim, H.J., Zhang L., Sohn, L.L., and Dernburg, A.F.* (2023) A cooperative network at the nuclear envelope counteracts LINC-mediated forces during oogenesis in C. elegans. Science Advances doi: https://www.science.org/doi/10.1126/sciadv.abn5709
Oogenesis involves transduction of mechanical forces from the cytoskeleton to the nuclear envelope (NE). In Caenorhabditis elegans, oocyte nuclei lacking the single lamin protein LMN-1 are vulnerable to collapse under forces mediated through LINC (linker of nucleoskeleton and cytoskeleton) complexes. Here, we use cytological analysis and in vivo imaging to investigate the balance of forces that drive this collapse and protect oocyte nuclei. We also use a mechano-node-pore sensing device to directly measure the effect of genetic mutations on oocyte nuclear stiffness. We find that nuclear collapse is not a consequence of apoptosis. It is promoted by dynein, which induces polarization of a LINC complex composed of SUN-1 and ZYG-12. Lamins contribute to oocyte nuclear stiffness and cooperate with other inner nuclear membrane proteins to distribute LINC complexes and protect nuclei from collapse. We speculate that a similar network may protect oocyte integrity during extended oocyte arrest in mammals.
Kim, H.J., Liu, C., Zhang, L. and Dernburg, A.F.* (2023) MJL-1 is a nuclear envelope protein required for homologous chromosome pairing and regulation of synapsis during meiosis in C. elegans. Science Advances 9 (6), eadd1453 doi: https://www.science.org/doi/10.1126/sciadv.add1453
Interactions between chromosomes and LINC (linker of nucleoskeleton and cytoskeleton) complexes in the nuclear envelope (NE) promote homolog pairing and synapsis during meiosis. By tethering chromosomes to cytoskeletal motors, these connections lead to processive chromosome movements along the NE. This activity is usually mediated by telomeres, but in the nematode Caenorhabditis elegans, special chromosome regions called “pairing centers” (PCs) have acquired this meiotic function. Here, we identify a previously uncharacterized meiosis-specific NE protein, MJL-1 (MAJIN-Like-1), that is essential for interactions between PCs and LINC complexes in C. elegans. Mutations in MJL-1 eliminate active chromosome movements during meiosis, resulting in nonhomologous synapsis and impaired homolog pairing. This work suggests a common origin and/or functions of the chromosome-NE connection during meiosis.
Chenshu's PhD work (selected)
Liu, C.*, Zhu, R. and Mao, Y.* (2018) Nuclear actin polymerized by mDia2 confines centromere movement during CENP-A loading. iScience, doi: https://doi.org/10.1016/j.isci.2018.10.031
In mitosis, accurate segregation of chromosomes relies on the centromere, which is epigenetically defined by CENP-A. We have previously identified mDia2, a diaphanous formin protein that nucleates F-actin, to be essential for the stable incorporation of new CENP-A into centromeric nucleosomes. Here we demonstrate that mDia2-mediated formation of dynamic and short nuclear actin filaments in G1 phase nuclei is required to maintain CENP-A levels at the centromere. Nuclear actin filaments constrain centromere movement during CENP-A loading and are important for the timely turnover of the CENP-A loading chaperone HJURP. Our findings suggest that nuclear actin polymerized by mDia2 contributes to the physical environment conducive of CENP-A loading. This work establishes an important examples of how nuclear F-actin can facilitate the maintenance of genome stability and contributes to the emerging view of nuclear actin in regulating chromosome dynamics and genome organization.
Zhu, R., Liu, C. and Gundersen, G.* (2017) Nuclear positioning in migrating fibroblasts. Semin Cell Dev Biol, pii: S1084-9521(17)30497-4. doi: https://doi.org/10.1016/j.semcdb.2017.11.006
The positioning and movement of the nucleus has recently emerged as an important aspect of cell migration. Understanding of nuclear positioning and movement has reached an apogee in studies of fibroblast migration. Specific nuclear positioning and movements have been described in the polarization of fibroblast for cell migration and in active migration in 2D and 3D environments. Here, we review recent studies that have uncovered novel molecular mechanisms that contribute to these events in fibroblasts. Many of these involve a connection between the nucleus and the cytoskeleton through the LINC complex composed of outer nuclear membrane nesprins and inner nuclear membrane SUN proteins. We consider evidence that appropriate nuclear positioning contributes to efficient fibroblast polarization and migration and the possible mechanism through which the nucleus affects cell migration.
Liu, C., Mao, Y.* (2016) Diaphanous formin mDia2 regulates CENP-A levels at centromeres. The Journal of Cell Biology, vol.213 no.4 415–424, doi: https://doi.org/10.1083/jcb.201512034
Timelapse showing YFP-CENP-A level (pseudo-colored, blue is low, yellow is high) at centromeres as daughter cells enter the G1 phase of the next cell cycle. WT control on the left, mDia2 depleted cell on the right.
In higher eukaryotes, centromeres are epigenetically defined by centromere protein A (CENP-A), a specialized histone H3 variant. To maintain centromere identity against CENP-A dilution as DNA replicates and cell divides, newly synthesized CENP-A proteins are deposited at centromeres in early G1 phase of each cell cycle. However, how new CENP-A is loaded and stabilized remains unclear. Here, we identify mDia2, a formin protein, as essential for stable replenishment of new CENP-A at centromeres. Using interdisciplinary approaches, we demonstrate the spatiotemporal mechanisms by which mDia2 facilitates CENP-A loading. We also demonstrate how mDia2 works with known pathways that regulate CENP-A maintenance. This finding provides a novel and orthogonal perspective in understanding the epigenetic maintenance of centromere identity.
Liu, C., Chuang, J.-Z., Sung, C.-H., and Mao, Y.* (2015) A dynein independent role of Tctex-1 at the kinetochore. Cell Cycle, 14:9, 1379-1388, doi: https://doi.org/10.1080/15384101.2014.1000217
Accurate segregation of chromosomes in mitosis depends on dynamic and robust attachment between microtubules and the kinetochore, a proteinaceous structure assembled on the centromere of each chromosome. Dynein light chains are accessory subunits of the cytoplasmic dynein complex, a minus-end directed microtubule motor. Here, we demonstrate that the dynein light chain Tctex-1 associates with unattached kinetochores and is essential for accurate chromosome segregation. Tctex-1 knockdown in cells does not affect the localization and function of dynein at the kinetochore, but produces a prolonged mitotic arrest with a few misaligned chromosomes, which are subsequently missegregated during anaphase (see timelapse example, where chromosomes are marked by YFP-H2B). This function is independent of Tctex-1's association with dynein. The kinetochore localization of Tctex-1 is independent of the canonical ZW10-dynein pathway, but requires the Ndc80 complex. Thus, our findings reveal a dynein independent role of Tctex-1 at the kinetochore to enhance the stability of kinetochore-microtubule attachment.