Jun-yuan Ji, PhD
Education and Post-Graduate Training
Dr. Jun-yuan Ji received his BS in cell biology from Lanzhou University in 1994, and a MS in developmental biology from the Institute of Genetics and Developmental Biology at the Chinese Academy of Sciences in 1997, where he worked in the laboratory of Professor Fang-zhen Sun. He obtained his PhD in zoology from the University of Washington at Seattle in 2003 working with Professor Gerold Schubiger. He then did postdoctoral research in Professor Nicholas Dyson’s laboratory at Massachusetts General Hospital Cancer Center and Harvard Medical School. Ji joined the faculty at the college in 2009.
Our long-term goal is to understand the regulatory mechanisms of how the transcriptional machinery is fined-tuned by signaling pathways and environmental perturbations in different developmental, physiological, and pathological contexts. Using the fruit fly Drosophila melanogaster and cultured mammalian cells as the experimental systems, we combine genetic, cell biological, and biochemical approaches to elucidate the conserved molecular and genetic regulatory circuits that control gene expression, lipid homeostasis, cell growth and proliferation during normal development and tumorigenesis. These efforts have led to the following three major research topics in the lab.
- Context-specific functions of the CDK8 module: The primary area is in elucidating the context-specific roles of the CDK8 module, a highly conserved module of the transcription cofactor Mediator complex, which bridges DNA-bound transcription factors and RNA polymerase II (Pol II) in eukaryotes. The four subunits of the CDK8 module – CDK8, Cyclin C, MED12, and MED13 – are either mutated or amplified in cardiovascular diseases and a number of human cancers. Elucidating the function and regulation of the CDK8 module in different biological contexts is essential to understanding the pathological consequences of its misregulation and to the design of clinical strategies to target the kinase activities of CDK8 in treating these diseases. We have identified two new downstream targets of CDK8, SREBP (sterol regulatory element-binding protein) and EcR (ecdysone receptor), as well as one upstream regulatory pathway of CDK8-CycC (the insulin/mTOR signaling pathway). Our results suggest that CDK8 coordinately regulates lipid biosynthesis by repressing SREBP-activated transcription and developmental timing by activating EcR-activated gene expression during the larval-pupal transition. In collaboration with Drs. Fajun Yang and Jeffrey Pessin at the Albert Einstein College of Medicine, we have found a conserved role of CDK8 in phosphorylating and destabilizing SREBP in Drosophila and mammalian cells. Interestingly, CDK8 is stabilized by nutrient deprivation and destabilized by feeding, suggesting a novel link between dietary perturbations and the general transcriptional machinery. Furthermore, cdk8 mutants are hyper-sensitive to dietary perturbations, particularly proteins and several specific amino acids, likely through the inhibitory effects of mTOR on CDK8. Further analyses of CDK8 functions and regulation may provide important insights to better understand how dysregulation of the CDK8 module contributes tumorigenesis and other diseases.
- The roles of Wnt signaling in regulating lipid homeostasis: We are interested in dissecting how developmental genetic pathways regulate lipid homeostasis during Drosophila larval development. Together with Dr. Wei Du at the University of Chicago, we have identified peptide boronic acids (PBAs) as potent inhibitors of Wnt signaling and fat metabolism defects caused by hyperactive Wnt signaling. Through developmental genetic analyses of Axin mutants in Drosophila, we have observed that hyperactive Wnt activity disrupts the lipid homeostasis in Drosophila larvae, which can be potently mitigated by feeding the mutant larvae with Bortezomib and two additional PBAs. Interestingly, the suppressive effect of PBAs on hyperactive Wnt signaling is dependent on α-catenin: the rescue effect is abolished with the depletion of α-catenin in adipocytes. These results suggest that pharmacological modulation of β-catenin activity through α-catenin can potentially be an attractive approach to attenuate Wnt signaling in vivo.
- Epigenetic regulation of chromatin dynamics and gene expression: In an independent line of research, we have been interested in how chromatin dynamics is regulated in development. We performed the first systematic genetic analysis of dKdm2 mutant alleles and demonstrated that the Drosophila histone lysine demethylase dKdm2 gene is not an essential gene for viability and normal development, which has been confirmed by our newly generated dKdm2 null alleles using the CRISPR/Cas9 technique. In collaboration with Dr. Yong Zhang at the University of Nevada and Dr. Jian-quan Ni at the Tsinghua University, we have observed that dKDM2 is involved in regulating circadian rhythms in Drosophila. Further analyses of the molecular mechanisms of dKDM2 and its orthologs in vertebrates regarding the regulation of circadian rhythms will advance our understanding of the epigenetic regulations of circadian clocks.
Candidates interested in graduate study in the Ji laboratory at the Texas A&M University Health Science Center are encouraged to apply through the following programs:
- Li, X., Liu, M., Ren, X., Loncle, N., Wang, Q., Hemba-Waduge, R., Boube, M., Bourbon, H.-M. G., Ni, J.Q., and Ji, J.Y.# (2018) The Mediator CDK8-Cyclin C complex modulates vein patterning in Drosophila by stimulating Mad-dependent transcription. (# Corresponding author) Posted on bioRxiv, doi: https://doi.org/10.1101/360628
- Gao, X., Xie, X.J., Hsu, F.N., Li, X., Liu, M., Hemba-Waduge, R., Xu, W., and Ji, J.Y.# (2018) CDK8 mediates the dietary effects on developmental transition in Drosophila. Developmental Biology, accepted. (# Corresponding author)
- Qiao, H.H., Wang, F., Xu, R.G., Sun, J., Zhu, R., Mao, D., Ren, X., Wang, X., Jia, Y., Peng, P., Shen, D., Liu, L.P., Chang, Z., Wang, G., Li, S., Ji, J.Y., Liu, Q., Ni, J.Q. (2018) An efficient and multiple target transgenic RNAi technique with low toxicity in Drosophila. Nature Communications 9, 4160. DOI: 10.1038/s41467-018-06537-y
- Zheng Y.*, Xue, Y.*, Ren, X.*, Liu, M., Li,X., Jia, Y., Niu, Y., Ni, J.Q.#, Zhang, Y.#, and Ji, J.Y.# (2018) The lysine demethylase dKDM2 is non-essential for viability, but regulates circadian rhythms in Frontiers in Genetics 9: 354. doi: 10.3389/fgene.2018.00354. (* Equal contribution authors; # Corresponding authors)
- Zhang, T.*, Hsu, F.N.*, Xie X.J.*, Li, X., Liu, M., Gao, X., Pei, X., Liao, Y., Du, W.#, and Ji, J.Y.# (2017) Reversal of hyperactive Wnt signaling-dependent adipocyte defects by peptide boronic acids. Proc. Natl. Acad. Sci. USA, 114 (36): E7469-E7478 (* Equal contribution authors; # Corresponding authors)
- Xie, X.J., Hsu, F.N., Gao, X., Xu, W., Ni, J.Q., Xing, Y., Huang, L., Hsiao, H.C., Zheng, H., Wang, C., Zheng, Y., Xiaoli, A.M., Yang, F., Bondos, S.E., Ji, J.Y.# (2015) CDK8-Cyclin C mediates nutritional regulation of developmental transitions through the Ecdysone Receptor in PLoS Biology 13(7): e1002207. doi:10.1371/journal.pbio.1002207. (# Corresponding author)
- Abdulla, A., Zhang, Y., Hsu, F.N., Xiaoli, A.M., Zhao, X., Yang, E.S.T., Ji, J.Y., and Yang, F. (2014) Regulation of lipogenic gene expression by lysine-specific histone demethylase-1 (LSD1). Journal of Biological Chemistry 289, 29937-29947.
- Zheng, Y., Hsu, F.N., Xu, W., Xie, X.J., Ren, X., Gao, X., Ni, J.Q., and Ji, J.Y.#(2014) A developmental genetic analysis of the lysine demethylase KDM2 in Drosophila melanogaster. Mechanisms of Development 133, 36-53. (# Corresponding author)
- Xu, W.#, Amire-Brahimi, B., Xie, X.J., Huang, L., Ji, J.Y.# (2014) All-atomic molecular dynamic studies of human CDK8: Insight on A-loop, point mutations and binding with its partner CycC. Computational Biology and Chemistry 51, 1-14. (# Corresponding authors)
- Zhang, T., Liao, Y., Hsu, F.N., Zhang, R., Searle, J.S., Pei, X., Li, X., Ryoo, H.D., Ji, J.Y., Du, W. (2014) Elevated TORC1 activity mediates synthetic lethal interaction between deregulated Wnt signaling and Rb inactivation. PLoS Genetics 10, e1004357.
- Gu, W., Wang, C., Li, W., Zhou, J., Yuan, C., Xie, X.J., Addya, S., Kong, B.# and Ji, J.Y.# (2013) Tumor suppressive effects of CDK8 in endometrial cancer cells. Cell Cycle 12, 987-999. (# Corresponding authors)
- Ji, J.Y. #, Miles, W.O. Korenjak, M., Zheng, Y., and Dyson, N.J. (2012) In vivo regulation of E2F1 by Polycomb group genes in G3: Genes, Genomes, Genetics 2, 1651-1660. (# Corresponding author)
- Zhao, X.*, Feng, D.*, Wang, Q.*, Abdulla, A., Xie, X.J., Zhou, J., Sun, Y., Yang, E.S., Liu, P., Vaitheesvaran, B., Bridges, L., Kurland, I., Strich, R., Ni, J.Q., Wang, C., Ericsson, J., Pessin, J.E., Ji, J.Y.#, and Yang, F.# (2012) Regulation of lipogenesis by cyclin-dependent kinase 8–mediated control of SREBP-1. Journal of Clinical Investigation 122, 2417-2427. (* Equal contribution authors; # Corresponding authors)
- Xu, W., and Ji, J.Y.# (2011) Dysregulation of CDK8 and Cyclin C in tumorigenesis. Journal of Genetics and Genomics 38, 439-452. (# Corresponding author)
- Ji, J.Y.#, and Dyson, N.J. (2010) Interplay between E2F-dependent transcription and cyclin-dependent kinases. G. Enders (ed.) Cell Cycle Deregulation in Cancer, Springer Science, pp 23-41. (# Corresponding author)
- Zhang, J.M., Ji, J.Y., Yu, M., Overholtzer, M., Smolen, G.A., Wang, R., Brugge, J.S., Dyson, N.J., and Haber, D.A. (2009) YAP-dependent secretion of amphiregulin contributes to its role in cellular transformation and progenitor expansion. Nature Cell Biology 11, 1444-1450.
- Morris, E.J. *, Ji, J.Y.*, Yang, F., Di Stefano, L., Herr, A., Moon, N.S., Kwon, E.J., Haigis, K.M., Näär, A.M., and Dyson, N.J. (2008) E2F1 represses β-catenin transcription and is antagonized by both pRB and CDK8. Nature 455, 552-556. (* Equal contribution authors)
- Di Stefano, L., Ji, J.Y., Moon, N.S., Herr, A., and Dyson, N. (2007) Mutation of Drosophila Lsd1 disrupts H3-K4 methylation, resulting in tissue-specific defects during development. Current Biology 17, 808-812.
- Ji, J.Y.#, Crest, J., and Schubiger, G. (2005). Genetic interactions between Cdk1-CyclinB and the Separase complex in Drosophila. Development 132, 1875-1884. (# Corresponding author)
- Ji, J.Y., Squrriell, J.M., and Schubiger, G. (2004). Both Cyclin B levels and DNA-replication checkpoint regulate the early embryonic mitoses in Drosophila. Development 131, 401-411. (Cover image)
- Ji, J.Y., Haghnia, M., Trusty, C., Goldstein, L.S.B., and Schubiger, G. (2002). A genetic screen for suppressors and enhancers of the Drosophila Cdk1-Cyclin B identifies maternal factors that regulate microtubule and microfilament stability. Genetics 162, 1179-1195.
- Mengmeng Liu, PhD - Postdoctoral Research Associate
- Rajitha-Udakara-Sampath Hemba-Waduge – Graduate Assistant Research
- Xiao Li - Graduate Assistant Research
- Luis López González – Visiting student from the University of Surrey
- Diana Luna Buitrago – Visiting student from the University of Surrey
- Bailey King – Undergraduate student