The Faculty

Focus

Mass spectrometry-based proteomics technologies, used to dissect PTM pathways

Education

Ph.D., The Rockefeller University, 1997

Research Summary

Laboratory of Proteomics and Protein Modifications

Post-translational modifications (PTMs) represent a major vehicle to diversify a cellular proteome, the inventory of all protein species in an organism. PTMs have critical roles in all the major cellular pathways and diseases. A protein can be potentially modified by more than 200 types of post-translational modifications, which are catalyzed by enzymes encoded by more than 5% of the genome in higher eukaryotes. A combination of a dozen PTM sites in a substrate protein could lead to more than a million possible protein structures with potentially different functions. Given the high abundance and diversities of PTMs, they are likely the most complex regulatory mechanisms in cells. Despite their critical roles in cells, little is known about their biology, except several most extensively studied PTMs. Functional characterizations of PTMs at the molecular level have been slow, largely due to a lack of suitable information infrastructure and technology infrastructure.
Our research aims to develop mass spectrometry-based proteomics technologies, and to use them to dissect PTM pathways. We are developing new mass spectrometry and bioinformatics tools for reliable, sensitive, and comprehensive analysis of proteins and PTMs. We are interested in dynamics analysis of diverse PTMs in order to understand their functions. We are using proteomics approach to characterize lysine acetylation, lysine propionylation, and lysine butyrylation pathways, the last two of which were recently discovered by us. We have begun applying a new bioinformatics tool, PTMap, also recently developed by us, to investigate PTM cross-talks. We also use powerful proteomics technologies in conjunction with biochemistry, molecular biology, and cell biology to decode PTM networks that have major implications for human health and are not amenable to conventional techniques.

Selected Papers

Tan, M., Luo,H., Lee, S., Jin, F., Yang, J.-S., Montellier, E., Buchou,T., Cheng, Z., Rousseaux, S., Rajagopal, N., Lu, Z., Ye, Z., Zhu, Q., Wysocka, J., Ye, Y., Khochbin, S., Ren, B., Zhao, Y., Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell, 2011. 146, 1016-1028

Peng, C., Lu, Z., Xie, Z., Cheng, Z., Chen, Y., Tan, M., Luo, H., Zhang, Y., He, W., Yang, K., Zwaans B.M., Tishkoff, D., Ho, L., Lombard, D., He, T.C., Dai, J., Verdin, E., Ye, Y., Zhao, Y. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics, 2011. In press.

Lu, J., Lin, Y., Sheu, J., Wu, J., Lee, F., Chen, Y., Lin, M., Chiang, F., Tai, T., Berger, S.L., Zhao, Y., Tsai, K., Zhu, H., Chuang, L., Boeke, J.D., A protein acetylation-phosphorylation signaling cascade coordinates growth and lifespan. Cell, 2011. 146, 969-979.

Zhang, Z., Tan, M., Xie, Z., Dai, L., Chen, Y., and Zhao, Y., Identification of lysine succinylation as a new post-translational modification. Nature Chem Biol, 2011. 7(1): p. 58-63.

Bajpai, R., Chen, D.A., Rada-Iglesias, A., Zhang, J., Xiong, Y., Helms, J., Chang, C.P., Zhao, Y., Swigut, T., and Wysocka, J., CHD7 cooperates with PBAF to control multipotent neural crest formation. Nature, 2010. 463: p. 958-62.

Li, L., Sun, L., Gao, F., Jiang, J., Yang, Y., Li, C., Gu, J., Wei, Z., Yang, A., Lu, R., Ma, Y., Tang, F., Kwon, S.W., Zhao, Y., Li, J., and Jin, Y., Stk40 links the pluripotency factor Oct4 to the Erk/MAPK pathway and controls extraembryonic endoderm differentiation. Proc Natl Acad Sci U S A, 2010. 107(4): p. 1402-1407.

Chen, Y., Chen, W., Cobb, M.H. and Zhao, Y., PTMap--a sequence alignment software for unrestricted, accurate, and full-spectrum identification of post-translational modification sites. Proc Natl Acad Sci U S A, 2009. 106(3): p. 761-6.

Cheng, Z., Tang, Y., Chen, Y., Kim, S., Liu, H., Li, S.S., Gu, W. and Zhao, Y., Molecular characterization of propionyllysines in non-histone proteins. Mol Cell Proteomics, 2009. 8(1): p. 45-52.

Lin, Y.Y., Lu, J.Y., Zhang, J., Walter, W., Dang, W., Wan, J., Tao, S.C., Qian, J., Zhao, Y., Boeke, J.D., Berger, S.L. and Zhu, H., Protein acetylation microarray reveals that NuA4 controls key metabolic target regulating gluconeogenesis. Cell, 2009. 136(6): p. 1073-84.

Peng, J.C., Valouev, A., Swigut, T., Zhang, J., Zhao, Y., Sidow, A. and Wysocka, J., Jarid2/Jumonji coordinates control of PRC2 enzymatic activity and target gene occupancy in pluripotent cells. Cell, 2009. 139(7): p. 1290-302.

Zhang, J., Sprung, R., Pei, J., Tan, X., Kim, S., Zhu, H., Liu, C.F., Grishin, N.V. and Zhao, Y., Lysine acetylation is a highly abundant and evolutionarily conserved modification in Escherichia coli. Mol Cell Proteomics, 2009. 8(2): p. 215-25.

Basu, A., Rose, K.L., Zhang, J., Beavis, R.C., Ueberheide, B., Garcia, B.A., Chait, B., Zhao, Y., Hunt, D.F., Segal, E., Allis, C.D. and Hake, S.B., Proteome-wide prediction of acetylation substrates. Proc Natl Acad Sci U S A, 2009. 106(33): p. 13785-13790.

Tang, Y., Zhao, W., Chen, Y., Zhao, Y. and Gu, W., Acetylation is indispensable for p53 activation. Cell, 2008. 133(4): p. 612-26.

Lin, Y.Y., Qi, Y., Lu, J.Y., Pan, X., Yuan, D.S., Zhao, Y., Bader, J.S. and Boeke, J.D., A comprehensive synthetic genetic interaction network governing yeast histone acetylation and deacetylation. Genes Dev, 2008. 22(15): p. 2062-74.

Chen, Y., Sprung, R., Tang, Y., Ball, H., Sangras, B., Kim, S.C., Falck, J.R., Peng, J., Gu, W. and Zhao, Y.,Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol Cell Proteomics, 2007. 6(5): p. 812-9.

Lee, J., Xu, Y., Chen, Y., Sprung, R., Kim, S.C., Xie, S. and Zhao, Y., Mitochondrial phosphoproteome revealed by an improved IMAC method and MS/MS/MS. Mol Cell Proteomics, 2007. 6(4): p. 669-76.

Chang, B., Chen, Y., Zhao, Y. and Bruick, R.K., JMJD6 is a histone arginine demethylase. Science, 2007. 318(5849): p. 444-7.

Kim, S.C., Sprung, R., Chen, Y., Xu, Y., Ball, H., Pei, J., Cheng, T., Kho, Y., Xiao, H., Xiao, L., Grishin, N.V., White, M., Yang, X.J. and Zhao, Y., Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol Cell, 2006. 23(4): p. 607-18.

Chien, Y., Kim, S., Bumeister, R., Loo, Y.M., Kwon, S.W., Johnson, C.L., Balakireva, M.G., Romeo, Y., Kopelovich, L., Gale, M., Jr., Yeaman, C., Camonis, J.H., Zhao, Y. and White, M.A., RalB GTPase-mediated activation of the IkappaB family kinase TBK1 couples innate immune signaling to tumor cell survival. Cell, 2006. 127(1): p. 157-70.

Qiu, Y., Zhao, Y., Becker, M., John, S., Parekh, B.S., Huang, S., Martinez, E.D., Chen, Y., Lu, H., Adkins, N.L., Georgel, P.T., Schiltz, P.L. and Hager, G.L., HDAC1 Acetylation is Linked to Progressive Modulation of Steroid Receptor Induced Gene Transcription. Mol Cell, 2006. 22(5): p. 669-679.