Yingming Zhao, Ph.D.

 

Laboratory of Proteomics and Precision Medicine

 

Overview

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 300 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.

Biological mass spectrometry and proteomics

Our research aims to develop mass spectrometry-based proteomics technologies, and to use them to dissect PTM pathways and to identify biomarkers. 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 identify and quantify substrates of novel lysine acylation pathways under diverse genetic background and extracellular environments. 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.

Lysine acylations, epigenetics and cellular metabolism

Our lab carried out first few mass spectrometry-based proteomic studies of lysine acetylation that led to identifying thousands of acetyllysine substrate peptides. These landmark works challenge a long-standing notion that lysine acetylation is restricted to nuclei and catalyze extensive investigation of non-nuclear functions of this modification pathway.  Our lab recently discovered eight types of new lysine acylation pathways: propionylation, butyrylation, crotonylation, malonylation, succinylation, glutarylation, 2-hydroxyisobutyrylation and 3-hydroxybutyrylation. They identified about 350 new histone marks, which more than doubles the tally of the previous known histone marks discovered during the first forty years of chromatin biology. They revealed numerous enzymes for the new PTM pathways, such as Sirt5 as a desuccinylase, demalonylase, and deglutarylase, as well as specific binding proteins (or “readers’) for the novel histone marks. His laboratory demonstrates that the new PTM pathways have critical roles in epigenetic regulation and cellular metabolism, and contribute to multiple inborn metabolic diseases.

Discovery of biomarkers, precision medicine and immune oncology

In the past few years, we have built a mass spectrometry-based proteomic technology and bioinformatics platforms for quantifying protein expression, protein modifications (e.g., phosphorylation and acetylation), and histone epigenetic marks. We have use the technology for identifying proteomic signatures that can classify tumors. We are also using proteomics approaches to identify tumor-specific antigens.  A major advantage of the proteomics-based strategy is that this approach enables to identify mutation-irrelevant biomarkers, which is a gold mine that has not yet been carefully explored. We are using these approaches for identifying predictive biomarkers for precision medicine and for immune oncotherapy.

References

2016

Sabari, B.R., Zhang, D., Allis, C.D., Zhao, Y., 2016. Metabolic regulation of gene expression through histone acylations. Nat. Rev. Mol. Cell Biol. doi:10.1038/nrm.2016.140

Xie, Z., Zhang, D., Chung, D., Tang, Z., Huang, H., Dai, L., Qi, S., Li, J., Colak, G., Chen, Y., Xia, C., Peng, C., Ruan, H., Kirkey, M., Wang, D., Jensen, L.M., Kwon, O.K., Lee, S., Pletcher, S.D., Tan, M., Lombard, D.B., White, K.P., Zhao, H., Li, J., Roeder, R.G., Yang, X., Zhao, Y., 2016. Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation. Mol. Cell 62, 194–206.doi:10.1016/j.molcel.2016.03.036

Goudarzi, A., Zhang, D., Huang, H., Barral, S., Kwon, O.K., Qi, S., Tang, Z., Buchou, T., Vitte, A L., He, T., Cheng, Z., Montellier, E., Gaucher, J., Curtet, S., Debernardi, A., Charbonnier, G., Puthier, D., Petosa, C., Panne, D., Rousseaux, S., Roeder, R.G., Zhao, Y**., Khochbin, S., 2016. Dynamic Competing Histone H4 K5K8 Acetylation and Butyrylation Are Hallmarks of Highly Active Gene Promoters. Mol. Cell 62, 169–180. doi:10.1016/j.molcel.2016.03.014

Li, Y., Sabari, B.R., Panchenko, T., Wen, H., Zhao, D., Guan, H., Wan, L., Huang, H., Tang, Z., Zhao, Y., Roeder, R.G., Shi, X., Allis, C.D., Li, H., 2016. Molecular Coupling of HistoneCrotonylation and Active Transcription by AF9 YEATS Domain. Mol. Cell 62, 181–193.doi:10.1016/j.molcel.2016.03.028

Xiong, X., Panchenko, T., Yang, S., Zhao, S., Yan, P., Zhang, W., Xie, W., Li, Y., Zhao, Y., Allis, C.D., Li, H., 2016. Selective recognition of histone crotonylation by double PHD fingers of MOZ and DPF2. Nat. Chem. Biol. 12, 1111–1118. doi:10.1038/nchembio.2218

Martínez-Reyes, I., Diebold, L.P., Kong, H., Schieber, M., Huang, H., Hensley, C.T., Mehta, M.M., Wang, T., Santos, J.H., Woychik, R., Dufour, E., Spelbrink, J.N., Weinberg, S.E., Zhao, Y., DeBerardinis, R.J., Chandel, N.S., 2016. TCA Cycle and Mitochondrial Membrane Potential Are Necessary for Diverse Biological Functions. Mol. Cell 61, 199–209doi:10.1016/j.molcel.2015.12.002

Kaczmarska, Z., Ortega, E., Goudarzi, A., Huang, H., Kim, S., Márquez, J.A., Zhao, Y., Khochbin, S., Panne, D., 2017. Structure of p300 in complex with acyl-CoA variants. Nat Chem Biol 13, 21–29. doi:10.1038/nchembio.2217

Respuela, P., Nikolić, M., Tan, M., Frommolt, P., Zhao, Y., Wysocka, J., Rada-Iglesias, A., 2016. Foxd3 Promotes Exit from Naive Pluripotency through Enhancer Decommissioning and Inhibits Germline Specification. Cell Stem Cell 18, 118–133. doi:10.1016/j.stem.2015.09.010

Wang, S.-J., Li, D., Ou, Y., Jiang, L., Chen, Y., Zhao, Y., Gu, W., 2016. Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression. Cell Rep 17, 366–373.doi:10.1016/j.celrep.2016.09.022

Zhao, D., Guan, H., Zhao, S., Mi, W., Wen, H., Li, Y., Zhao, Y., Allis, C.D., Shi, X., Li, H., 2016. YEATS2 is a selective histone crotonylation reader. Cell Res 26, 629–632. doi:10.1038/cr.2016.49

Liu, K., Li, F., Han, H., Chen, Y., Mao, Z., Luo, J., Zhao, Y., Zheng, B., Gu, W., Zhao, W., 2016. Parkin Regulates the Activity of Pyruvate Kinase M2. J. Biol. Chem. 291, 10307–10317.doi:10.1074/jbc.M115.703066

Washburn, M.P., Zhao, Y., Garcia, B.A., 2016. Reshaping the Chromatin and Epigenetic Landscapes with Quantitative Mass Spectrometry. Mol. Cell Proteomics 15, 753–754.doi:10.1074/mcp.E116.058602

Aramsangtienchai, P., Spiegelman, N.A., He, B., Miller, S.P., Dai, L., Zhao, Y., Lin, H., 2016. HDAC8 Catalyzes the Hydrolysis of Long Chain Fatty Acyl Lysine. ACS Chem. Biol. 11, 26852692. doi:10.1021/acschembio.6b00396

Qian, L., Nie, L., Chen, M., Liu, P., Zhu, J., Zhai, L., Tao, S., Cheng, Z., Zhao, Y., Tan, M., 2016. Global Profiling of Protein Lysine Malonylation in Escherichia coli Reveals Its Role in Energy Metabolism. J. Proteome Res. 15, 2060–2071. doi:10.1021/acs.jproteome.6b00264

Sun, M., Xu, J., Wu, Z., Zhai, L., Liu, C., Cheng, Z., Xu, G., Tao, S., Ye, B.-C., Zhao, Y., Tan, M., 2016. Characterization of Protein Lysine Propionylation in Escherichia coli: Global Profiling, Dynamic Change, and Enzymatic Regulation. J. Proteome Res. 15, 4696–4708. doi:10.1021/acs.jproteome.6b00798

Morozumi, Y., Boussouar, F., Tan, M., Chaikuad, A., Jamshidikia, M., Colak, G., He, H., Nie, L.,Petosa, C., de Dieuleveult, M., Curtet, S., Vitte, A.-L., Rabatel, C., Debernardi, A., Cosset, F.-L.,Verhoeyen, E., Emadali, A., Schweifer, N., Gianni, D., Gut, M., Guardiola, P., Rousseaux, S., Gérard, M., Knapp, S., Zhao, Y., Khochbin, S., 2016. Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells. J Mol Cell Biol 8, 349–362. doi:10.1093/jmcb/mjv060

Kwon, O.K., Kim, S.J., Lee, Y.-M., Lee, Y.-H., Bae, Y.-S., Kim, J.Y., Peng, X., Cheng, Z., Zhao, Y.,Lee, S., 2016. Global analysis of phosphoproteome dynamics in embryonic development of zebrafish (Danio rerio). Proteomics 16, 136–149. doi:10.1002/pmic.201500017