Yingming Zhao, Ph.D.

Research Summary

Laboratory of Proteomics and Protein Post-translational modifications


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. 


Recent Publications

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Huang H, Lin S, Garcia BA, Zhao Y, Quantitative Proteomic Analysis of Histone Modifications. Chem Rev. 2015 Mar 25;115(6):2376-418. doi: 10.1021/cr500491u.

Colak G, Pougovkina O, Dai L, Tan M, Te Brinke H, Huang H, Cheng Z, Park J, Wan X, Liu X, Yue WW, Wanders RJ, Locasale JW, Lombard DB, de Boer VC, Zhao Y, Proteomic and Biochemical Studies of Lysine Malonylation Suggest Its Malonic Aciduria-associated Regulatory Role in Mitochondrial Function and Fatty Acid Oxidation. Mol Cell Proteomics. 2015 Nov;14(11):3056-71. doi: 10.1074/mcp.M115.048850. Epub 2015 Aug 28.

Hirschey MD, Zhao Y, Metabolic Regulation by Lysine Malonylation, Succinylation, and Glutarylation. Mol Cell Proteomics. 2015 Sep;14(9):2308-15.

Wu Z, Cheng Z, Sun M, Wan X, Liu P, He T, Tan M, Zhao Y, A chemical proteomics approach for global analysis of lysine monomethylome profiling. Mol Cell Proteomics. 2015 Feb;14(2):329-39. doi: 10.1074/mcp.M114.044255.

Zhao Y, Garcia BA, Comprehensive Catalog of Currently Documented Histone Modifications. Cold Spring Harb Perspect Biol. 2015 Sep 1;7(9):a025064. doi: 10.1101/cshperspect.a025064.

Kang Y, Zhou XE, Gao X, He Y, Liu W, Ishchenko A, Barty A, White TA, Yefanov O, Han GW, Xu Q, de Waal PW, Ke J, Tan MH, Zhang C, Moeller A, West GM, Pascal BD, Van Eps N, Caro LN, Vishnivetskiy SA, Lee RJ, Suino-Powell KM, Gu X, Pal K, Ma J, Zhi X, Boutet S, Williams GJ, Messerschmidt M, Gati C, Zatsepin NA, Wang D, James D, Basu S, Roy-Chowdhury S, Conrad CE, Coe J, Liu H, Lisova S, Kupitz C, Grotjohann I, Fromme R, Jiang Y, Tan M, Yang H, Li J, Wang M, Zheng Z, Li D, Howe N, Zhao Y, Standfuss J, Diederichs K, Dong Y, Potter CS, Carragher B, Caffrey M, Jiang H, Chapman HN, Spence JC, Fromme P, Weierstall U, Ernst OP, Katritch V, Gurevich VV, Griffin PR, Hubbell WL, Stevens RC, Cherezov V, Melcher K, Xu HE, Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature. 2015 Jul 30;523(7562):561-7. doi: 10.1038/nature14656. Epub 2015 Jul 22.

Sabari BR, Tang Z, Huang H, Yong-Gonzalez V, Molina H, Kong HE, Dai L, Shimada M, Cross JR, Zhao Y, Roeder RG, Allis CD, Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol Cell. 2015 Apr 16;58(2):203-15. doi: 10.1016/j.molcel.2015.02.029. Epub 2015 Mar 26.

He QL, Titov DV, Li J, Tan M, Ye Z, Zhao Y, Romo D, Liu JO, Covalent Modification of a Cysteine Residue in the XPB Subunit of the General Transcription Factor TFIIH Through Single Epoxide Cleavage of the Transcription Inhibitor Triptolide. Angew Chem Int Ed Engl. 2015 Feb 2;54(6):1859-63. doi: 10.1002/anie.201408817.

Torres MJ, Pandita RK, Kulak O, Kumar R, Formstecher E, Horikoshi N, Mujoo K, Hunt CR, Zhao Y, Lum L, Zaman A, Yeaman C, White MA, Pandita TK, Role of the Exocyst Complex Component Sec6/8 in Genomic Stability. Mol Cell Biol. 2015 Nov 1;35(21):3633-45. doi: 10.1128/MCB.00768-15. Epub 2015 Aug 17.

Morozumi Y, Boussouar F, Tan M, Chaikuad A, Jamshidikia M, Colak G, He H, Nie L, Petosa C, de Dieuleveult M, Curtet S, Vitte AL, Rabatel C, Debernardi A, Cosset FL, Verhoeyen E, Emadali A, Schweifer N, Gianni D, Gut M, Guardiola P, Rousseaux S, Gérard M, Knapp S, Zhao Y, Khochbin S. Atad2 is a generalist facilitator of chromatin dynamics in embryonic stem cells. J Mol Cell Biol. 2015 Oct 12. pii: mjv060.

Liu H, Yue J, Huang H, Gou X, Chen SY, Zhao Y, Wu X. Regulation of Focal Adhesion Dynamics and Cell Motility by EB2 and Hax1 Complex. J Biol Chem. 2015 Nov 2. pii: jbc.M115.671743.

Cluntun AA, Huang H, Dai L, Liu X, Zhao Y, Locasale JW. The rate of glycolysis quantitatively mediates specific histone acetylation sites. Cancer Metab. 2015 Sep 23;3:10. doi: 10.1186/s40170-015-0135-3. eCollection 2015.

Kwon OK, Kim S, Lee YM, Lee YH, Bae YS, Kim JY, Peng X, Cheng Z, Zhao Y, Lee S. Global analysis of phosphoproteome dynamics in embryonic development of zebrafish (Danio rerio). Proteomics. 2015 Oct 9. doi: 10.1002/pmic.201500017.


Huang H, Sabari BR, Garcia BA, Allis CD, Zhao Y, SnapShot: Histone Modifications. Cell. 2014 Oct 9;159(2):458-458.e1. doi: 10.1016/j.cell.2014.09.037.

Dai L, Peng C, Montellier E, Lu Z, Chen Y, Ishii H, Debernardi A, Buchou T, Rousseaux S, Jin F, Sabari BR, Deng Z, Allis CD, Ren B, Khochbin S, Zhao Y, Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark. Nat Chem Biol. 2014, doi: 10.1038/nchembio.1497.

Tan M, Peng C, Anderson KA, Chhoy P, Xie Z, Dai L, Park J, Chen Y, Huang H, Zhang Y, Ro J, Wagner GR, Green MF, Madsen AS, Schmiesing J, Peterson BS, Xu G, Ilkayeva OR, Muehlbauer MJ, Braulke T, Mühlhausen C, Backos DS, Olsen CA, McGuire PJ, Pletcher SD, Lombard DB, Hirschey MD, Zhao Y, Lysine Glutarylation Is a Protein Posttranslational Modification Regulated by SIRT5. Cell Metab. 2014, 19, 605-17.

Wu Z, Cheng Z, Sun M, Wan X, Liu P, He T, Tan M, Zhao Y, A Chemical Proteomics Approach for Global Analysis of Lysine Mono-Methylation. Mol Cell Proteomics. 2014, pii: mcp.M114.044255.

Tang S, Huang G, Fan W, Chen Y, Ward JM, Xu X, Xu Q, Kang A, McBurney MW, Fargo DC, Hu G, Baumgart-Vogt E, Zhao Y, Li X. SIRT1-Mediated Deacetylation of CRABPII Regulates Cellular Retinoic Acid Signaling and Modulates Embryonic Stem Cell Differentiation. Mol Cell. 2014 Aug 20. pii: S1097-2765(14)00604-2. doi: 10.1016/j.molcel.2014.07.011.

He QL, Titov DV, Li J, Tan M, Ye Z, Zhao Y, Romo D, Liu JO, Covalent Modification of a Cysteine Residue in the XPB Subunit of the General Transcription Factor TFIIH Through Single Epoxide Cleavage of the Transcription Inhibitor Triptolide. Angew Chem Int Ed Engl. 2014, doi: 10.1002/anie.201408817.

Kazgan N, Metukuri MR, Purushotham A, Lu J, Rao A, Lee S, Pratt-Hyatt M, Lickteig A, Csanaky I, Zhao Y, Dawson PA, Li X. Intestine-specific Deletion of Sirt1 in Mice Impairs DCoH2-HNF1α-FXR Signaling and Alters Systemic Bile Acid Homeostasis. Gastroenterology, 2014, 146, 1006-16.

Xu G, Wang J, Wu Z, Qian L, Dai L, Wan X, Tan M, Zhao Y, Wu Y., SAHA regulates histone acetylation, butyrylation and protein expression in neuroblastoma. J Proteome Res. 2014, DOI: 10.1021/pr500497e

 Luo X, Wang B, Tang F, Zhang J, Zhao Y, Li H, Jin Y. Wwp2 targets SRG3, a scaffold protein of the SWI/SNF-like BAF complex, for ubiquitination and degradation. Biochem Biophys Res Commun, 2014, 443, 1048-53.

Sun H, Chen X, Yuan F, Liu J, Zhao Y, Chen SY. Involvement of seven in absentia homolog-1 in ethanol-induced apoptosis in neural crest cells. Neurotoxicol Teratol. 2014 Sep 3;46C:26-31. doi: 10.1016/j.ntt.2014.08.006.

Zhang Y, Wu Z, Wan X, Liu P, Zhang J, Ye Y, Zhao Y, Tan M, Comprehensive Profiling of Lysine Acetylome in Staphylococcus aureus. Sci China Chem. In Press.


Park J, Chen Y, Tishkoff DX, Peng C, Tan M, Dai L, Xie Z, Zhang Y, Zwaans BM, Skinner ME, Lombard DB, Zhao Y, SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways. Mol Cell, 2013, 50, 919-30.

Colak G, Xie Z, Zhu AY, Dai L, Lu Z, Zhang Y, Wan X, Chen Y, Cha YH, Lin H, Zhao Y, Tan M. Identification of lysine succinylation substrates and the succinylation regulatory enzyme CobB in Escherichia coli. Mol Cell Proteomics, 2013, 12, 3509-20.

Chen Y, Colak G, Zhao Y, SILAC-Based Quantification of Sirt1-Responsive Lysine Acetylome. Methods Mol Biol, 2013, 1077, 105-20.

Dobbin MM, Madabhushi R, Pan L, Chen Y, Kim D, Gao J, Ahanonu B, Pao PC, Qiu Y, Zhao Y, Tsai LH, SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons. Nat Neurosci, 2013, 16, 1008-15.

Hattori T, Taft JM, Swist KM, Luo H, Witt H, Slattery M, Koide A, Ruthenburg AJ, Krajewski K, Strahl BD, White KP, Farnham PJ, Zhao Y, Koide S, Recombinant antibodies to histone post-translational modifications. Nat Methods, 2013, 18. doi: 10.1038/nmeth.2605.

Montellier E, Boussouar F, Rousseaux S, Zhang K, Buchou T, Fenaille F, Shiota H, Debernardi A, Héry P, Curtet S, Jamshidikia M, Barral S, Holota H, Bergon A, Lopez F, Guardiola P, Pernet K, Imbert J, Petosa C, Tan M, Zhao Y, Gérard M, Khochbin S., Chromatin-to-nucleoprotamine transition is controlled by the histone H2B variant TH2B. Genes Dev, 2013, 27, 1680-92.

Lee S, Tan M, Dai L, Kwon OK, Yang JS, Zhao Y, Chen Y, MS/MS of synthetic peptide is not sufficient to confirm new types of protein modifications. J Proteome Res, 2013, 12, 1007-13.

 Liao B, Zhong X, Xu H, Xiao F, Fang Z, Gu J, Chen Y, Zhao Y, Jin Y, Itch, an E3 ligase of Oct4, is required for embryonic stem cell self-renewal and pluripotency induction. J Cell Physiol, 2013, 228, 1443-51.



Xie, Z., Dai, J., Dai, L., Tan, M., Cheng, Z., Wu,Y., Boeke, J. D., Zhao, Y., Lysine succinylation and lysine malonylation in histones. Mol Cell Proteomics, 2012, 11, 100-7. 

Chen, Y., Zhao, W., Yang, J.S., Cheng, Z., Luo, H., Lu, Z., Tan, M., Gu, W., and Zhao, Y., Quantitative acetylome analysis reveals the roles of SIRT1 in regulating diverse substrates and cellular pathways. Mol Cell Proteomics, 2012, 11, 1048-62.

Li, N., Kon, N., JIang, L., Tan, M., Ludwig, T., Zhao, Y., Baer, R., W., G., Tumor suppression in the absence of p53-mediated cell cycle arrest, apoptosis, and senescence. Cell, 149, 1269-83

Qiang, L., Wang, L., Kon, N., Lee, S., Zhao, Y., Gu, W., Farmer, S.R., Accili, D., Brown remodeling of white adipocytes by SirT1-dependent deacetylation of PPARγ. Cell, 2012, 150, 620-32.

Choi, M.C., Cohen, T.J., Barrientos, T., Wang, B., Simmons, B.J., Li, M., Yang, J.S., Cox, G.A., Zhao, Y., Yao, T.P., A direct HDAC4-MAP kinase crosstalk activates neurogenic muscle atrophy. Mol Cell, 2012, 47, 1-11.

Liu, J., Yan, J., Jiang, S., Wen, J., Chen, L., Zhao, Y., Lin, A., Site-specific ubiquitination is required for relieving the transcription factor Miz1-mediated suppression on TNF-α-induced JNK activation and inflammation. Proc Natl Acad Sci U S A, 2012, 109, 191-6.

Montellier, E., Rousseaux, S., Zhao, Y., Khochbin S. Histone crotonylation specifically marks the haploid male germ cell gene expression program. Bioessays, 2012, 34, 187-93.



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, 1016-28.

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

Peng, C., Lu, Z., Xie, Z., Cheng, Z., Chen, Y., Tan, M., Luo, H., Zhang, Y., He, W., Yang, K., Zwaans, B.M. 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, 10, M111.012658.

Lu, J.-Y., Lin, Y.-Y., Sheu, J.-C., Wu, J.-T., Lee, F.-J., Chen, Y., Lin M.-I, Chiang, F.-T., Tai, T.-Y., Berger, S. L., Zhao, Y., Tsai K.-S., Zhu, H., Chuang, L.-M., and Boeke, J. D., Acetylation of Yeast AMPK Controls Intrinsic Aging Independently of Caloric Restriction. Cell, 2011, 146, 969-979.

Ghosh, S., Zhang, J., Zhao, Y., DePamphilis, M.L., and Vassilev, A.P., Assembly of the human origin recognition complex occurs through independent nuclear localization of its components. J Biol Chem, 2011, 286, 23831-41.

Samant, S.A., Courson, D.S., Sundaresan, N.R., Pillai, V.B., Tan, M., Zhao, Y., Shroff, S.G., Rock, R.S. and Gupta, M.P., HDAC3-dependent reversible lysine acetylation of cardiac myosin heavy chain isoforms modulates their enzymatic and motor activity. J Biol Chem, 2011, 286, 5567-77.

He, B.-C., Gao, J.-L., Zhang, B.-Q., Luo, Q., Shi, Q., Kim, S.H., Huang, E., Gao, Y., Yang, K., Wagner, E.R., Wang, L., Tang, N., Luo, J., Liu, X., Li, M., Shen, J., Luther, G., Hu, N., Zhou, Q., Luu, H.H., Haydon, R.C., Zhao, Y., He, T.C.,  Tetrandrine Inhibits Wnt/b-Catenin Signaling and Suppresses Tumor Growth of Human Colorectal Cancer. Mol Pharmacol2011, 79, 211-9.

Chu,C., Hou, H., Zhang, J., Phu, L., Loktev, A.V.,  Kirkpatrick, D.S.,  Jackson, P.J., Zhao, Y., Zou, H., A novel acetylation of β-tubulin by San modulates microtubule polymerization via down-regulating tubulin incorporation, Mol Biol Cell, 2011, 22, 448-56.

Lu, Z., Cheng, Z., Zhao, Y., Volchenboum ,S.L., Bioinformatic analysis and post-translational modification crosstalk prediction of lysine acetylation. PLoS One, 2011, 6, e28228.

Li, X., Wang, Q., Pan, N., Lee, S., Zhao, Y., Chait, B., Yue, Z. Phosphorylation-Dependent 14-3-3 Binding to LRRK2 Is Impaired by Common Mutations of Familial Parkinson’s Disease. PLoS One, 2011, 6, e17153.

Song, H., Li, C.-W., Labaff, A.M., Lim, S.-O., Li, L., Kan, S.-F., Chen, Y., Zhang, K., Lang, J., Xie, X., Wang, Y., Huo, L., Hsu, S.-C., Chen, X.,Zhao, Y., Hung, M.-C., Acetylation of EGF receptor contributes to tumor cell resistance to Histone deacetylase inhibitors. Biochem Biophys Res Commun, 2011, 404, 68–73.