Zhe Yang

Zhe Yang

Associate Professor

zyang@med.wayne.edu

313-577-1294

Zhe Yang

Position Title

 Associate Professor

Education

Ph.D. Institute of Biophysics, Chinese Academy of Sciences, Beijing, P. R. China, 1999

Postdoctoral:
Emory University, Atlanta, GA, 2007
University of California at San Diego, La Jolla, CA, 2002

Graduate

Accepting new M.S. students in fall of 2020: Yes
Accepting new Ph.D. students in fall of 2020: Yes

Office Location

4340 Scott Hall

Research

Dr. Yang's research involves the structure and function of SET and MYND domain-containing (SMYD) proteins.

Research Focus

 We are interested in the structure and function of a special class of protein lysine methyltransferases – the SMYD protein family. SMYD proteins are an exciting field of study as they are linked to many types of cancer-related pathways. Cardiac and skeletal muscle development and function also depend on SMYD proteins opening a possible avenue for cardiac-related treatment. We recently found that SMYD5, the most unique member of the SMYD protein family, is co-expressed with genes involved in both nucleolar and mitochondrial rRNA processing in Pan-Cancer analysis. Our Pan-Cancer analysis was performed over 10,000 TCGA samples across 33 cancer types, aimed to identify the conserved gene co-expression networks that are common to all cancers. We found that the SMYD5-co-expressed genes are significantly enriched in the nucleolus and mitochondrion. Those nucleolar genes have more focused functions and mainly involved in regulating 18S pre-rRNA processing, while the functions of the mitochondrial genes range from regulating RNA stability and processing to playing roles in protein import into mitochondrial matrix, assembly of mitochondrial respiratory complexes and mitochondrial membrane organization. Previously, glycolysis was considered as the main source of energy for cancer growth, while new evidence showed that the metabolic plasticity and ability to rapidly adjust the balance between glycolytic and mitochondrial energy production is key to tumor survival and metastasis. Our Pan-Cancer analysis challenges both these paradigms in terms of the SMYD5 gene co-expression modules. The high level of intermodular connections suggests that the nucleolar rRNA processing and mitochondrial functions are universally metabolically coupled, which is common to all cancers, regardless of tumor origin, disease stage, or treatment. We are testing a new hypothesis that SMYD5 is a bona fide RNA binding protein that coordinates nucleolar rRNA processing with mitochondrial ribosome synthesis in response to nutrient availability. We will show that the dynamic crosstalk between the O-GlcNAcylation and phosphorylation regulates SMYD5 shuttling between the nucleus and mitochondria. Serving as a nutrient sensor, SMYD5 is crucial for the maintenance of cancer cell homeostasis by ensuring a precise balance between nuclear rRNA processing, glucose availability, and mitochondrial energy production. Breaking this balance may offer an exciting new approach for anti-Pan-Cancer therapy. 

Publications

1. Jahanbakhsh, S., Dekhne, M., Kohan-Ghadr, H., Bai, D., Awonuga, A., Morris, R., Yang, Z. and Abu-Soud H. The inhibition of lactoperoxidase catalytic activity through mesna (2-mercaptoethane sodium sulfonate). Journal of Inorganic Biochemistry,12(203):110911. doi: 10.1016/j.jinorgbio.2019.110911 (2020).
2. Zhang, Y., Li, C. and Yang, Z. Is MYND Domain-Mediated Assembly of SMYD3 Complexes Involved in Calcium Dependent Signaling? Frontiers in Molecular Biosciences. 6:121. doi:10.3389/fmolb.2019.00121 (2019).
3. Buaduang, N., Chansuwan, W., Towatana, N. Yang, Z. and Sirinupong, N. Tilapia Protein Hydrolysate Enhances Transepithelial Calcium Transport in Caco2 cells. Functional Foods In Health & Disease. doi: 10.31989/ffhd.v9i10.651 (2019).
4. Hu, W., Xu, L., Chen, B., Ou, S., Muzzarelli, K., Hu, D., Li, Y., Yang, Z., Griend, D., Prins, G. and Qin, Z. Targeting prostate cancer cells with enzalutamide-HDAC inhibitor hybrid drug 2-75. Prostate, 79(10):1166-1179. doi:10.1002/pros.23832 (2019).
5. Mu Zhang, Chen Hu, Niko Moses, Joshua Haakenson, Shengyan Xiang, Daniel Quan, Bin Fang, Yang, Z., Wenlong Bai, Gerold Bepler, Guo-Min Li, and Xiaohong Zhang. HDAC6 regulates DNA damage response via deacetylating MLH1. Journal of Biological Chemistry, doi:10.1074/jbc.RA118.006374 (2019).
6. Muzzarelli, K. M., Kuiper, B. D., Spellmon, N., Brunzelle, J. S., Hackett, J., Amblard, F., Zhou, S., Liu, P., Kovari, I. A., Yang, Z., Schinazi, R. F. & Kovari, L. C. Structural and antiviral studies of the human norovirus GII.4 protease. Biochemistry, doi:10.1021/acs.biochem.8b01063 (2019).
7. Cornett, E. M., Dickson, B. M., Krajewski, K., Spellmon, N., Umstead, A., Vaughan, R. M., Shaw, K. M., Versluis, P. P., Cowles, M. W., Brunzelle, J., Yang, Z., Vega, I. E., Sun, Z. W. & Rothbart, S. B. A functional proteomics platform to reveal the sequence determinants of lysine methyltransferase substrate selectivity. Science advances, 4:eaav2623, doi:10.1126/sciadv.aav2623 (2018).
8. Munkanatta Godage, D. N. P., VanHecke, G. C., Samarasinghe, K. T. G., Feng, H. Z., Hiske, M., Holcomb, J., Yang, Z., Jin, J. P., Chung, C. S. & Ahn, Y. H. SMYD2 glutathionylation contributes to degradation of sarcomeric proteins. Nature communications, 9:4341, doi:10.1038/s41467-018-06786-x (2018).
9. Kuiper, B. D., Muzzarelli, K. M., Keusch, B. J., Holcomb, J., Amblard, F., Liu, P., Zhou, S., Kovari, I. A., Yang, Z., Schinazi, R. F. & Kovari, L. C. Expression, Purification and Characterization of a GII.4 Norovirus Protease from Minerva Virus. Infectious disorders drug targets, 18:224-232 (2018).
10. Holcomb, J., Doughan, M., Spellmon, N., Lewis, B., Perry, M., Zhang, Y., Nico, L., Wan, J., Chakravarthy, S., Shang, W., Miao, Q., Stemmler, T. and Yang, Z. SAXS analysis of a soluble cytosolic NgBR construct including extracellular and transmembrane domains. PLoS One, 13(1):e0191371 (2018).
11. Wu, J., Xiang, S., Zhang, M., Fang, B., Huang, H., Kwon, O., Zhao, Y., Yang, Z., Bai, W., Bepler, G. and Zhang, X. Histone deacetylase 6 (HDAC6) deacetylates extracellular signal-regulated kinase 1 (ERK1) and thereby stimulates ERK1 activity. Journal of Biological Chemistry, 293(6):1976-1993 (2018).
12. Dai, X., Thiagarajan, D., Fang, J., Shen, J., Annam, N., Jiang, H., Ju, D., Xie, Y., Zhang, K., Tseng, Y., Yang, Z., Rishi, A., Li, H., Yang, M. and Li, L. SM22α suppresses cytokine-induced inflammation and the transcription of NF-κB inducing kinase (Nik) by modulating SRF transcriptional activity in vascular smooth muscle cells. PLoS One, 12(12):e0190191 (2017).
13. Jeelanna, R., Jahanbakhsh, S., Kohan-Ghadr, H., Thakur, M., Khan, S., Aldhaheri, S., Yang, Z., Andreana, P., Morris, R. and Abu-Soud, H. Mesna (2-Mercaptoethane Sodium Sulfonate) Functions as a Regulator of Inflammation Through Myeloperoxidase. Free Radical Biology & Medicine, 110:54-62 (2017).
14. Kuiper, B., Slater, K., Spellmon, N., Holcomb, J., Medapureddy, P., Muzzarelli, K., Yang, Z., Ovadia, R, Amblard, F., Kovari, I., Schinazi, R., Kovari, L. Increased activity of unlinked Zika virus NS2B/NS3 protease compared to linked Zika virus protease. Biochem Biophys Res Commun, S0006-291X(17):30567-3, (2017).
15. Spellmon, N., Holcomb, J., Niu, A., Choudhary, V., Sun, X., Zhang, Y., Wan, J., Doughan, M., Hayden, S., Hachem, F., Brunzelle, F., Li, C. and Yang, Z. Structural basis of PDZ-mediated chemokine receptor CXCR2 scaffolding by guanine nucleotide exchange factor PDZ-RhoGEF. Biochem Biophys Res Commun, doi: 10.1016/j.bbrc.2017.02.010, (2017).
16. Spellmon, N., Sun, X., Xue, W., Holcomb, J., Chakravarthy, S., Shang, W., Edwards, B., Sirinupong, N., Li, C. and Yang, Z. New open conformation of SMYD3 implicates conformational selection and allostery. AIMS Biophysics, 4(1):1-18, doi: 10.3934/biophy.2017.1.1, (2017).
17. Zaidan, A., Spellmon, N., Choudhary, V., Li, C. and Yang, Z. N-Lysine Methyltransferase SMYD. Encyclopedia of Signaling Molecules, Chapter 101729-1, Springer (2017).
18. Zhao, B., Hu, W., Kumar, S., Gonyo, P., Rana, U., Liu, Z., Wang, B., Duong, WQ., Yang, Z., Williams, CL. and Miao, QR. The Nogo-B receptor promotes Ras plasma membrane localization and activation. Oncogene, January 9, doi: 10.1038/onc.2016.484, (2017).
19. Yu, H., Jiang, Y, Liu, L., Shan, W., Chu, X., Yang, Z. and Yang, ZQ. Integrative genomic and transcriptomic analysis for pinpointing recurrent alterations of plant homeodomain genes and their clinical significance in breast cancer. Oncotarget, December 31, doi: 10.18632/oncotarget.14402, (2016).
20. Doughan, M., Spellmon, N., Li, C. and Yang, Z. SMYD proteins in immunity: dawning of a new era. AIMS Biophysics, 3(4):450-455, (2016).
21. Hou, Y., Guan, X., Yang, Z. and Li, C. Emerging role of cystic fibrosis transmembrane conductance regulator - an epithelial chloride channel in gastrointestinal cancers. World Journal of Gastrointestinal Oncology, 8(3):282-282, (2016).
22. Guan, X., Hou, Y., Sun, F., Yang, Z. and Li, C. Dysregulated Chemokine Signaling in Cystic Fibrosis Lung Disease: A Potential Therapeutic Target. Current Drug Targets, 17(13):1535-44, (2016).
23. Sirinupong, N. and Yang, Z. Epigenetics in Cystic Fibrosis: Epigenetic Targeting of a Genetic Disease. Current Drug Targets, 16(9):976-87, (2015).
24. Jiang, Y., Holcomb, J., Spellmon, N. and Yang, Z. Purification of Histone Lysine Methyltransferase SMYD2 and Co-crystallization with a Target Peptide from Estrogen Receptor α. Methods in Molecular Biology, 1366:207-17, (2015).
25. Sun, X., Spellmon, N., Holcomb, J., Xue, W., Li, C. and Yang, Z. Epigenetic landscape in embryonic stem cell. Stem Cells in Toxicology and Medicine, Wiley (2015).
26. Hou, Y., Guan, X., Farooq, S., Sun, X., Wang, P., Yang, Z., and Li, C. Stem Cell Therapeutics for Cardiovascular Diseases. Stem Cells in Toxicology and Medicine, Wiley (2015).
27. Spellmon, N., Sun, X., Sirinupong, N., Edwards, B., Li, C. and Yang, Z. Molecular Dynamics Simulation Reveals Correlated Inter-Lobe Motion in Protein Lysine Methyltransferase SMYD2. PLoS ONE, 10(12):e0145758, (2015).
28. Yang, Z., Sun, F. and Li, C. Emerging Molecular Targets for the Treatment of Cystic Fibrosis. Current Drug Targets, 16(9):922, (2015).
29. Sirinupong, N. and Yang, Z. Bioactive Food Components as Dietary Intervention for Cystic Fibrosis. Current Drug Targets, 16(9):988-92, (2015).
30. Spellmon, N., Holcomb, J., Trescott, L., Sirinupong, N. and Yang, Z. Structure and Function of SET and MYND Domain-Containing Proteins. International Journal of Molecular Sciences, 16:1406-1428, (2015).
31. Holcomb, J., Spellmon, N., Trescott, L., Sun, F., Li, C. and Yang, Z. PDZ Structure and Implication in Selective Drug Design against Cystic Fibrosis. Current Drug Targets, 16(9):945-50, (2015).
32. Trescott, L., Holcomb, J., Spellmon, N., Mcleod, C., Aljehane, L., Sun, F., Li, C. and Yang, Z. Targeting the Root Cause of Cystic Fibrosis. Current Drug Targets, 16(9):933-44, (2015).
33. Hou, Y., Wu, Y., Farooq, S.M., Guan, X., Liu, Y., Oblak, J.J., Holcomb, J., Jiang, Y., Strieter, R.M., Lasley, R.D., Arbab, A.S., Sun, F., Li, C. and Yang, Z. A Critical Role of CXCR2 PDZ-mediated Interactions in Endothelial Progenitor Cell Homing and Angiogenesis. Stem Cell Research, 14:133-143, (2014).
34. Margaret, R., Jiang, Y., Holcomb, J., Trescott, L., Spellmon, N., Sirinupong, N. and Yang, Z. SMYD2 Structure and Function: A Multispecificity Protein Lysine Methyltransferase. Journal of Cytology and Molecular Biology, 1(2):7, (2014).
35. Jiang, Y., Holcomb. J., Trescott, L., Rice, M. and Yang, Z. Structural Dissection of Cardiogenic and Myogenic SMYD Proteins. Experimental and Clinical Cardiology, Jul 31, (2014).
36. Yang, Z and Li, C. Is Smyd1 Involved in Vasculature?. Austin Biomark Diagn, 1(1):2, (2014).
37. Abu-Soud, H., Maitra, D., Shaeib, F., Khan, S., Byun, J., Abdulhamid, I., Yang, Z., Saed, G., Diamond, M., Andreana and P., Pennathur, S. Disruption of heme-peptide covalent cross-linking in mammalian peroxidases by hypochlorous acid. Journal of Inorganic Biochemistry, doi: 10.1016/j.jinorgbio.2014.06.018, (2014).
38. Holcomb, J., Jiang, Y., Guan, X., Trescott, L., Lu, G., Hou, Y., Wang, S., Brunzelle, J., Sirinupong, N., Li, C. and Yang, Z. Crystal Structure of the NHERF1 PDZ2 Domain in Complex with the Chemokine Receptor CXCR2 Reveals Probable Modes of PDZ2 Dimerization. Biochem Biophys Res Commun, 446(1):399-403, (2014).
39. Jiang, Y., Trescott, L., Holcomb, J., Zhang, X., Brunzelle, J., Sirinupong, N., Shi, X. and Yang, Z. Structural Insights into Estrogen Receptor Alpha Methylation by Histone Methyltransferase SMYD2, a Cellular Event Implicated in Estrogen Signaling Regulation. Journal of Molecular Biology, S0022-2836:00101-6, (2014).
40. Jiang, Y., Wang, S., Holcomb, J., Trescott, L., Guan, X., Hou, Y., Brunzelle, J., Sirinupong, N., Li, C. and Yang. Z. Crystallographic Analysis of NHERF1-PLCβ3 Interaction Provides Structural Basis for CXCR2 Signaling in Pancreatic Cancer. Biochem Biophys Res Commun, 446(2):638-43, (2014).
41. Holcomb, J., Jiang, Y., Lu, G., Trescott, L., Brunzelle, J., Sirinupong, N., Li, C., Naren, A. and Yang, Z. Structural Insights into PDZ-mediated Interaction of NHERF2 and LPA2, a Cellular Event Implicated in CFTR Channel Regulation. Biochem Biophys Res Commun, 446(1):399-403, (2014).
42. Jiang, Y., Lu, G., Trescott, L., Hou, Y., Guan, X., Wang, S., Stamenkovich, A., Brunzelle, J., Sirinupong, N., Spaller, M., Li, C. and Yang, Z. New Conformational State of NHERF1-CXCR2 Signaling Complex Captured by Crystal Lattice Trapping. PLoS ONE 8(12):e81904, (2013).
43. Zhang, X., Tanaka, K., Li, J., Yang, J., Peng, D., Jiang, Y., Yang, Z., Barton, M., Wen, H., and Shi, X. Regulation of estrogen receptor α by SMYD2-mediated protein methylation. Proc. Natl. Acad. Sci. USA, 110:17284-9, (2013).
44. Lu, G., Wu, Y., Jiang, Y., Wang, S., Hou, Y., Guan, X., Brunzelle, J., Sirinupong, N., Sheng, S., Li, C. and Yang, Z. Structural Insights into Neutrophilic Migration Revealed by the Crystal Structure of the Chemokine Receptor CXCR2 in Complex with the First PDZ Domain of NHERF1. PLoS ONE 8(10):e76219, (2013).
45. Jiang, Y., Sirinupong, N., Brunzelle, J. and Yang, Z. Crystal structures of histone and p53 methyltransferase SmyD2 reveal a conformational flexibility of the autoinhibitory C-terminal domain. PLoS ONE, 6:e21640, (2011).
46. Sirinupong, N., Brunzelle, J., Doko, E. and Yang, Z. Structural insights into the autoinhibition and posttranslational activation of histone methyltransferase SmyD3. Journal of Molecular Biology, 406:149-159, (2011).
47. Sirinupong, N., Brunzelle, J., Ye, J., Pirzada, A., Nico, L. and Yang, Z. Crystal structure of cardiac-specific histone methyltransferase SmyD1 reveals unusual active site architecture. Journal of Biological Chemistry, 285:40635-40644, (2010).
48. Ooi SK, Qiu C, Bernstein E, Li K, Jia D, Yang, Z., Erdjument-Bromage H, Tempst P, Lin SP, Allis CD, Cheng X and Bestor TH. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature, 448:714-7, (2007).
49. Horton, J.R., Zhang, X., Maunus, R., Yang, Z., Wilson, G.G., Roberts, R.J. and Cheng, X. DNA nicking by HinP1I endonuclease: bending, base flipping and minor groove expansion. Nucleic Acids Res, 34:939-48, (2006).
50. Yang, Z., Horton, J.R., Maunus, R., Wilson, G.G., Roberts, R.J. and Cheng, X. Structure of HinP1I endonuclease reveals a striking similarity to the monomeric restriction enzyme MspI. Nucleic Acids Res, 33:1892-901, (2005).
51. Yang, Z., Shipman, L., Zhang, M., Anton, B.P., Roberts, R. and Cheng, X. Structural Characterization and Comparative Phylogenetic Analysis of Escherichia coli HemK, a Protein (N5)-glutamine Methyltransferase. Journal Molecular Biology, 340:695-706, (2004).
52. Bestor, T., Bourc'his, D., Cheng, X., Qiu. C. and Yang, Z. Meiotic Catastrophe and Transponson Remanimation in DNMT3L-Deficient Male Germ Cells. Cold Spring Harbor Symposia on Quantitative Biology - COLD SPRING HARBOR SYMP, 69:1-1 (2004).
53. Sawada, K., Yang, Z., Zhang, X. and Cheng, X. Crystal Structure of Yeast Histone H3 K79 Methyltransferase Dot1p. Journal of Biological Chemistry, 279:43296-306, (2004).
54. Yang, Z., Horton, J.R., Zhou, L., Zhang, X.L., Dong, A., Zhang, X., Schlagman, S.L., Kossykh, V., Hattman, S. and Cheng, X. Structure of the Bacteriophage T4 DNA Adenine Methyltransferases. Nature Structural Biology, 10:849-855, (2003).
55. Zhang, X., Yang, Z., Khan, S.I., Horton, J.R., Tamaru, I., Selker, E.U. and Cheng, X. Structural Basis for the Product Specificity of Histone Lysine Methyltransferases. Molecular Cell, 12:177-185, (2003).
56. Yang, Z., Pandi, L. and Doolittle, R.F. Crystal Structure of Fragment Double-D from Cross-Linked Lamprey Fibrin Reveals Isopeptide Linkages Across an Unexpected D-D Interface. Biochemistry, 41:15610-15617, (2002).
57. Yang, Z., Spraggon, G., Pandi, L., Everse, E.J., Riley, M. and Doolittle, R.F. Crystal Strucure of Fragment D from Lampery Fibrinogen Complexed with Peptide Gly-His-Arg-Pro-Amide. Biochemistry, 41:10218-10224, (2002).
58. Doolittle, R.F., Yang, Z. and Mochalkin, I. Crystal Structure Studies on Fibrinogen and Fibrin. Annals of the New York Academy of Sciences, 936:31-43, (2001).
59. Yang, Z., Kollman, J.M., Pandi, L. and Doolittle, R.F. Crystal Structure of Native Chicken Fibrinogen at 2.7Å Resolution. Biochemistry, 40:12515-12523, (2001).
60. Yang, Z., Mochalkin, I. and Doolittle, R.F. A Model of Fibrin Formation Based on Crystal Structures of Fibrinogen and Fibrin Fragments Complexed with Synthetic Peptides. Proc. Natl. Acad. Sci. USA, 97:14156-14161, (2000).
61. Yang, Z., Mochalkin, I., Veerapandian, I., Riley, M. and Doolittle, R.F. Crystal Structure of Native Chicken Fibrinogen at 5.5Å Resolution. Proc. Natl. Acad. Sci. USA, 97:3907-3912, (2000).
62. Yang, Z., Ye, S., Jing, G., Gui, L. and Liang, D. Crystal Structure of an N-Terminal Fragment SNR141 of Staphylococcal Nuclease R Refined at 1.9 Angstrom Resolution. Progress in Natural Science, 9:617-622, (1999).

 

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