Biochemistry and Molecular Biology
Penn State Science
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Yanming Wang

Yanming Wang

Main Content

  • Associate Professor of Biochemistry and Molecular Biology
454 North Frear Laboratory
University Park, PA 16802
Phone: (814) 865-3775

Research Interests

Epigenetic histone modifications in cell differentiation and cancer

Research Summary

Epigenetic Histone Modifications in Cell differentiation and Cancer

Gene regulation is an important molecular mechanism underlying cell growth, proliferation, differentiation, and death during normal development and life cycles. Abnormality in gene expression such as epigenetic silencing of tumor suppressor genes can have harmful consequences leading to cell over-proliferation and tumorigenesis. In eukaryotic cells, chromatin is composed of histone proteins and DNA molecules and is the physiological template upon which gene regulation occurs. A flurry of recent literature demonstrates that covalent histone modifications contribute greatly to epigenetic form of gene regulation.

My long-term research interest is to study how histone modifications regulate gene expression during normal development and under disease conditions. Currently, I investigate the role of histone citrullination catalyzed by peptidylarginine deiminase 4 (PAD4) in transcriptional repression of tumor suppressor genes, as well as a unique role of histone hyper-citrullination in antibacterial innate immunity mediated by a highly decondensed chromatin structure termed neutrophil extracellular traps (NETs). In a 2004 Science paper, I showed that PAD4 regulates histone Arg methylation by converting mono-methyl-Arg to citrulline via a novel demethylimination reaction in addition to its well-established activity to convert protein Arg residues to citrulline. PAD4 is a fascinating molecule to study not only because of its dual enzymatic activities in catalyzing deimination of Arg and demethylimination of methyl-Arg but also because of its health relevance to human diseases including cancers and rheumatoid arthritis. Studies from my group over the last several years have contributed significantly to our current knowledge of the physiological function of PAD4 as well as the involvement of PAD4 over-expression in the etiology of cancers and rheumatoid arthritis. We are poised to make novel discoveries in several research areas (see below) and contribute to the field of chromatin structure and function.

(1) Histone modifications in p53-target gene expression
(2) Design and evaluate the therapeutic potential of PAD4 inhibitors
(3) Histone hyper-citrullination in higher order chromatin structure and innate immunity
(4) OKL38 and its cooperation with p53 in regulating mitochondria structure and function

Wang figure 1

Figure 1. Epigenetic histone modifications at multiple of histone sites regulate chromatin function, such as transcription of tumor suppressor genes and chromatin folding/unfolding, which are two research directions pursued in my laboratory.

Wang figure 2

Figure 2. Our current research is focused on understanding basic cell biological and developmental processes, such as stem cell pluripotency, cell differentiation and dedifferenation, as well as cell cycle and death. By understanding the epigenetic mechanisms underlying these normal processes, we hope to generate new tools prevent and control human diseases, such as cancer and autoimmune diseases.

Selected Publications

  • Martinod K, Demers M, Fuchs TA, Wong SL, Brill A, Gallant M, Hu J, Wang Y., and Wagner DD. (2013) Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis. Proc. Natl. Acad. Sci.  110:8674-9.

  • Zhu H, Wang Y, Wang Y, Zhao S, Zhao M*, Gui L, Xu W, Chen XA, Wang Y.*, and Peng S*. (2013) Folded conformation, cyclic pentamer, nano-structure and PAD4 binding mode of YW3-56. Journal of Physical Chemistry C 117:10070-10078.  (*authors of correspondence)

  • Wang S and Wang Y. (2013) Peptidylarginine deiminases in citrullination, gene regulation, healthiness and pathogenesis. Biochim. Biophys. Acta 1829:1126-1135

  • Hu J and Wang Y. (2013) p53 and the PWWP domain containing effector proteins in chromatin damage repair.  Cell & Developmental Biology 2:112.doi:10.4172/2168-9296.1000112 (Invited review)

  • Wang Y *, Li P*, Wang S*, Hu J, Chen XA, Wu J, Fisher M, Oshaben K, Zhao N, Gu Y, Chen G#, Wang Y#. (2012) Anticancer PAD inhibitors regulate autophagy and the mammalian target of rapamycin complex 1 activity. Journal of Biological Chemistry. 287:25941-53. (*authors of equal contribution, # authors of correspondence) 
  • Hu J*, Yao H*, Gan F, Tokarski A, and Wang Y. (2012) Coordination of OKL38 and p53 in apoptosis induction by regulating mitochondria morphology and function. PLoS ONE 7(8):e43362. (*authors of equal contribution).
  • Leshner M, Wang S, Lewis C, Zheng H, Chen XA,Santy L, and Wang Y. (2012) PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Frontiers in Immunology. 3:307.
  • Xu L, Hu J, Zhao Y, Hu J, Xiao J, Wang Y, Ma D, and Chen Y. (2012) PDCD5 interacts with p53 and functions as a positive regulator in the p53 pathway. Apoptosis 17:1235-1245.
  • Shi K, Edwards PS, Hu J, Xu Q, Wang Y, Psaltis D, and Liu Z. (2012) Holographic coherent anti-stokes raman scattering bio-imaging. Biomedical Optics Express 3:1744-1749.
  • Li P, Hu J, and Wang Y. (2012) Methods for analyzing histone citrullination in chromatin structure and gene regulation. Methods in Molecular Biology 809:473-488.
  • Wu L, Zee BM, Wang Y, Garcia BA, and Dou Y. (2011) The RING finger protein MSL2 in the MOF complex is an E3 ubiquitin ligase for H2B K34 ubiquitylation and is important for H3 K4/K79 methylation and transcription activation. Molecular Cell 43:132-144.

  • Wu H, Zeng H, Lam R, Tempel W, Amaya MF, Xu C, Dombrovski L, Qiu W, Wang Y, and Min J. (2011) Structural and histone binding ability characterizations of human PWWP domains. PloS ONE 6(6): e18919.

  • Liu Y, Chan YM, Wu J, Chen C, Benesi A, Hu J, Wang Y, and Chen G. (2011) Chemical Synthesis of a bisphosphorylated mannose-6-phosphate N-glycan and its facile monoconjugation with human carbonic anhydrase II for in vivo fluorescence imaging. Chembiochem. 12:685-690.
  • Joo HY, Jones A, Yang C, Zhai L, Smith AD, Zhagn Z, Chandrasekharan MB, Sun ZW, Renfrow M, Wang Y, Chang C, and Wang H. (2011) Regulation of histone H2A and H2B deubiquitination andXenopus development by USP12 and USP46. Journal of Biological Chemistry 286:7190-7201.

  • Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, and Wang Y. (2010) PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. Journal of Experimental Medicine 207:1853-62.

  • Li P, Wang D, Yao H, Doret P, Hao G, Shen Q, Qiu H, Zhang X, Wang Y, Chen G, and Wang Y. (2010) Coordination of PAD4 and HDAC2 in the regulation of p53 target gene expression. Oncogene 29:3153-62.
  • Jin Y, Xia M, Saylor CM, Narayan K, Kang J, Wiest DL, Wang Y, and Xiong N. (2010) Intrinsic programming of thymic T cells for specific peripheral tissue localization. Journal of Immunology. 185:7156-7160. 

  • Chow, O.A., von Kockritz-Blickwede, M., Bright, A.T., Hensler, M.E., Zinkernagel, A.S., Cogen, A.L., Gallo, R.L., Monestier, M., Wang, Y., Glass, C.K., and Nizet, V. (2010) Statins enhance formation of phagocyte extracellular traps. Cell Host & Microbe 18:445-454.
  • Wang Y*, Li M, Stadler S, Correll S, Li P, Wang D, Hayama R, Leonelli L, Han H, Grigoryev S, Allis CD, Coonrod SA* (2009) Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol. 184:205-13.  (*Correspondence authors).
  • Hao G, Wang D, Gu J, Shen Q, Gross SS, and Wang Y. (2009) Neutral loss of isocyanic acid in peptide CID spectra: a novel diagnostic marker for mass spectrometry identification of protein citrullination. J Am Soc Mass Spectr. 20:723-7.
  • Yao H, Li P, Venters BJ, Zheng S, Thompson PR, Pugh BF, Wang Y. (2008) Histone Arg modifications and p53 regulate the expression of OKL38, a mediator of apoptosis. J. Biol. Chem. 283, 20060-8.
  • Li P, Yao H, Zhang Z, Li M, Luo Y, Thompson PR, Gilmour DS, Wang Y. (2008) Regulation of p53 target gene expression by peptidylarginine deiminase 4. Mol Cell Biol. 28, 4745-58.
  • Wang, Y, Wysocka J, Sayegh, J, Lee, YH, Perlin JR, Leonelli, L, Sonbuchner, LS, McDonald, CH, Cook, RG, Dou, Y, Roeder, RG, Clarke, S, Stallcup, MR, Allis, CD, Coonrod, SA (2004) Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306, 279-83. (Featured in Nature News and Views (2004), Nature, 431:637-9)
  • Wang, Y, Zhang, W, Jin, Y, Johansen, J, and Johansen, KM (2001) The JIL-1 tandem kinase mediates histone H3 phosphorylation and is required for maintenance of chromatin structure in Drosophila. Cell 105: 433-43.