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My lab has a long-standing interest in cell division and cytoskeleton. In recent years, the findings we have made have broadened our research scope to include three research areas: 1. The mechanism of cell division. 2. The mechanism of genome organization in development, homeostasis, and aging. 3. The influence of cell morphogenesis on cell fate decisions. We use a wide range of tools and systems, including genetics in model organisms, cell culture, biochemistry, proteomics, genomics, in our research. Here I briefly summarize each of the research areas with selected publications at the end of the summary. For a full list of publications please refer to the complete Publication list.
You can watch a video about our study of the connection between nuclear lamins and age-associated inflammation (Cell Press PaperFlick "Aging Brings on Inflammation" or Cell Press YouTube.
The way a progenitor cell partitions itself during cell division has a profound influence on the behavior and fate of its daughter cells. Understanding this partitioning requires us to study both the mechanism of equal chromosome segregation and the means a dividing cell segregates critical cell fate determinants into daughter cells. The mitotic spindle apparatus is one of the most complex cellular machines consisting of microtubules, microtubule-associated proteins (MAPs), and motors. The spindle also associates with many poorly defined proteins and membranes. Historically these spindle-associated materials are called the spindle matrix. The importance of the spindle matrix and the value of studying it have remained a subject of debate.
We have uncovered protein complexes called γ-tubulin ring complex (TuRC) and γ-tubulin small complex (γTuSC) that mediate microtubule nucleation and organization in mitotic and interphase cells. Through the study of microtubule nucleation, we became fascinated by the more complex and dynamic behaviors of microtubules during mitotic spindle assembly. By using the powerful Xenopus egg extract, we and others have uncovered an important signaling pathway mediated by the nuclear small GTPase Ran that regulates multiple aspects of cell division. We showed that RanGTPase also regulates the assembly of the spindle matrix containing lamin-B. Based on our studies, we propose that RanGTP and the spindle matrix promote both spindle assembly and orientation. Consistent with this, we show that lamin-B, a spindle matrix component, regulates spindle orientation in neural stem cells in the developing mouse brain. Lamin-B may do so in part by regulating centrosome positioning.
The complexity of the spindle matrix has made the study of its structure and function relationship very difficult, which contributes to the debate of its function and even existence. By studying another spindle matrix component BuGZ, which we found through proteomic analyses of the Xenopus spindle matrix, we recently show that protein phase transition represents a biophysical property of the spindle matrix. The phase transition of BuGZ along spindle microtubules promotes spindle matrix assembly, which in turn facilitates spindle microtubule assembly by concentrating tubulin. This finding should open the door to further characterize the structure and function of the spindle matrix in cell division.
Genome Organization in Development, Tissue Homeostasis, and Aging
The nuclear lamina and chromatin-bound proteins are known to regulate genome organization in interphase cells, yet how cells in different lineages acquire and maintain their unique genome architecture has remained poorly understood. We use various tools in genetics, genomics (such as ChIP-seq and RNA-seq), cell biology, and biochemistry to study how genomes obtain their organization in stem cells (including ES cells) and differentiated cells isolated from tissues. We also analyze whether such organization plays a role in lineage specification or terminal differentiation, how such organization is maintained in adulthood, and whether genome dis-organization leads to age-associated diseases. For example, our recent studies demonstrate that lamin-B (the major structural component of the nuclear lamina) is not required for early lineage specification during development, but it is essential for proper organogenesis. Aging-associated lamin-B loss in Drosophila fat bodies (equivalent to human fat and liver) leads to system inflammation and gut hyperplasia. These and other ongoing studies in the lab are allowing us to dissect the role of genome organization in the context of development, tissue function, and aging.
The Influence of Cell Morphogenesis on Cell Fate Decisions
We use mouse embryos to study how the morphology and physical property of a cell influence its transcriptional network during differentiation. The development of the pre-implantation embryo affords a unique opportunity for this study because the first lineage specification occurs in a small number of initially similar cells independent of signal induction from other tissues. By applying two-photon live-imaging and computational modeling and tracking, we have uncovered unique cellular behaviors that are coupled with lineage specification during pre-implantation development. These observations have allowed us to use two-photon microscopy to further analyze how various physical and chemical perturbations of cell morphology influence the expression of lineage specification genes. As the nuclear lamina is connected to both chromatin and cytoskeleton, we hope that these efforts will help to uncover the morphological code that directs tissue building.
- Zheng Y, Jung MK, & Oakley BR (1991). γ-tubulin is present in Drosophila melanogaster and Homo sapiens and is associated with the centrosome (link is external). Cell 65:817-823.
- Zheng Y, Wong ML, Alberts B, & Mitchison TJ (1995). A γ-tubulin ring complex from the unfertilized egg of Xenopus laevis can nucleate microtubule assembly in vitro. Nature 378:578-583.
- Wilde A & Zheng Y (1999). Stimulation of Microtubule Aster Formation and Spindle Assembly in Xenopus Egg Extracts by the Small GTPase Ran (link is external). Science 284:1359-1362.
- Wiese C & Zheng Y (2000). A New Function for the γ-tubulin Ring Complex as a Microtubule Minus-end Cap (link is external). Nature Cell Biology 2:358-364.
- Wilde A, Lizarraga S, Zhang L, Wiese C, Gliksman N,Walczak C, & Zheng Y (2001). Ran stimulates spindle assembly by changing microtubule dynamics and the balance of motor activities (link is external). Nature Cell Biology 3:221-227.
- Wiese C, Wilde A, Adam S, Moore M, Merdes A, & Zheng Y (2001). Role of Importin-beta Coupling Ran to Downstream Targets in Microtubule Assembly (link is external). Science 291:653-656.
- Tsai MY, Wiese C, Cao K, Martin OC, Donovan P, Ruderman J, Prigent C, & Zheng Y (2003). A Ran-signaling pathway mediated by the mitotic kinase Aurora A in spindle assembly (link is external). Nature Cell Biology 5:242-248.
- Cao K, Nakajima R, Meyer HH, & Zheng Y (2003). The AAA-ATPase Cdc48/p97 regulates spindle disassembly at the end of mitosis (link is external). Cell 115:355-367.
- Li HY & ZhengY (2004). Mitotic phosphorylation of RCC1 is essential for RanGTP gradient production and spindle assembly in mammalian cells. Genes and Development 18:512-527.
- Vong QP, Cao K, Li HY, Iglesias PA, & Zheng Y (2005). Chromosome Alignment and Segregation Regulated by Ubiquitination of Survivin (link is external). Science 310:1499-1504.
- Tsai M-Y, Wang S, Heidinger JM, Shumaker D, Adam SA, Goldman RD, & Zheng Y (2006). A Mitotic Lamin B Matrix Induced by RanGTP Required for Spindle Assembly (link is external). Science 311:1887-1893.
- Li M, Tsai MY, Lu B, Chen R, Yates III JR, Zhu X, & Zheng Y (2009). A Requirement of Nudel and Dynein for Spindle Matrix Assembly during Spindle Morphogenesis (link is external). Nature Cell Biology 11:247-256.
- Kim Y, Sharov AA, McDole K, Cheng M, Hao H, Fan C-M, Gaiano N, Ko MSH, & Zheng Y (2011). Mouse ES cells do not need any lamins but proper organogenesis requires lamin-Bs (link is external). Science 334:1706-1710.
- Jia J, Zheng X, Hu G, Cui K, Zhang A, Zhang J, Du Y, Liu C, Zhao K, and Zheng Y (2012). Regulation of pluripotency and self-renewal of ES cells through epigenetic threshold modulation and mRNA pruning. Cell 151:576–589.
- Chen H, Chen X, and Zheng Y (2013). The nuclear lamina regulates germline stem cell niche organization via modulation of EGFR signaling (link is external). Cell Stem Cell 13:73-86.
- Jiang H, He X, Wang S, Jia J, Wan Y, Wang Y, Zeng R, Yates J 3rd, Zhu X, and Zheng Y (2014). A microtubule-associate zinc finger protein, BuGZ, regulated mitotic chromosome alignment by ensuring Bub3 stability and kinetochore targeting (link is external). Developmental Cell 28:268-281.
- Chen H, Zheng X, and Zheng Y (2014). Age-associated loss of lamin-B leads to systemic inflammation and gut hyperplasia. Cell 159:829-843.
- Jiang H, Wang S, Huang Y, He X, Cui H, Zhu X, and Zheng Y (2015). Phase Transition of Spindle-Associated Protein Regulate Spindle Apparatus Assembly. Cell, 163:108-122.
- Zheng X, Zheng Y. CsoreTool: Fast Hi-C compartment analysis at high resolution. Bioinformatics. (2017) 34:1568-1570. Epub: doi: 10.1093/bioinformatics/btx802.
- Huang Y, Li T, Ems-McClung SC, Walczak CE, Prigent C, Zhang X, and Zheng Y (2018). Aurora A activation in mitosis promoted by BuGZ. Journal of Cell Biology 217: 1077-116. Epub 2017 Oct 26th.
- Zheng X, Hu J, Yue S, Kristiani L, Kim M, Kim Y, and Zheng Y (2018). Lamins organize the three dimensional genome from nuclear periphery in ES cells. Molecular Cell 71: 802-815.