Associate Professor of Biochemistry and Biophysics
Faculty Director, Quantitative Proteomics Center for Disease Marker Discovery
(PhD - Penn State University)
Chen Lab Website
HONORS & AWARDS
- Presidential Early Career Award for Scientists and Engineers (PECASE), 1999
- Department of Energy Early Career Award for Scientists and Engineers, 1999
- The 2001 Patent & Licensing Awards, Los Alamos National Lab, 2002
Our research focuses on both developments and applications of unconventional and transformative technology of systems biology to elucidate the molecular mechanisms underlying pathogenesis of various inflammation-associated human diseases such as cancer, asthma, immune disorders. Our ultimate goal is to mechanistically derive novel, precise disease markers for early diagnosis and therapeutic intervention.
Current areas of interest:
1. Development of system biology platform for novel cancer marker discovery.
In the efforts to establish multiple proteomics platforms in a pipeline capable of a multi-angle dissection of the regulatory pathways/mechanisms under pathological circumstances, since 1999 our group has been pioneering in developing a quantitative proteomic technique, Amino Acid-Coded mass Tagging (AACT) or SILAC named by others. This AACT-assisted, mass spectrometry(MS)-based technology has been proved to be very useful for global analysis of quantitative proteome changes including expression, post-translational modifications, and protein-protein interactions. Currently, with the colleagues at Washington University we are one of the five NCI-funded centers of The Clinical Proteomic Tumor Analysis Consortium (CPTAC)http://proteomics.cancer.gov/programs/cptacnetwork where we join the efforts to define the proteins translated from cancer genomes in order to link genotype to proteotype and ultimately to discover novel cancer markers.
2. Discovery of new pathways involved in in Toll-like Receptor (TLR)-mediated pathogenesis.
At the first line of defense for immunosurveillance, toll-like receptors (TLRs) alerts the host and contains the invasion of pathogenic microorganisms by activating/mediating the innate immune signaling. However, through the underlying mechanisms largely unknown TLR-mediated inflammatory signaling can be double-edged swords, both protecting the host from infection or damage and promoting immunological pathogenesis. When dysregulated, TLR signaling promotes over-exuberant inflammation with severe pathological outcomes, such as organ failure or autoimmune diseases, on the other hand, to avoid harmful inflammation cells acquire tolerance and become less responsive to prolonged stimulation, which contributes clinically to immunosuppression and mortality associated with many chronic inflammatory diseases such as sepsis, asthma, and cancer. Given that the inflammatory signals of the stimulus/agonist recognition by TLRs are primarily conveyed to intracellular effector machinery through large numbers of the proteins that interact in either steady or transient manner, we have developed an array of ‘unbiased’, discovery-driven, sensitive methods of quantitative proteomics for phenotype-specific, pathway-wide screening of interacting proteins to resolve the complexities of TLR-mediated inflammatory signaling. By starting without pre-convinced notion or hypothesis, we have simultaneously identified many novel immunomodulators. The concurrent characterization of their functional roles in TLR signaling showed the physiologically relevant accuracy of our discovery proteomic approaches. Consequently, we have systematically expanded the view of TLR signal regulation by (1) providing both molecular and mechanistic illustrations of the timely modulation of TLR signaling by multi-protein interactions, (2) discovering specific post-translational modification (PTM) as the driving force for signal-associated, dynamic protein-protein interactions, and (3) developing a proteomics-based, ‘systems immunology’ platform generally applicable to both hypothesis generation and pathway/network-scale mechanistic elucidation. Recently, by mapping interactions of the protein network that underlies chronic inflammation, we found that PP2Ac disrupts the pro-inflammatory signaling pathway mediated by the complex of TLR4 and its intracellular adaptor MyD88. As a result of this disruption, both constitutively active PP2Ac and MyD88 move within the cellular nucleus, where they bound with the epigenetic machinery and alter the chromatin structure of a class of pro-inflammatory genes that leads to the silencing of this class of the genes
3. Epigenetic regulation of cell fate decision
DNA damage recognition/repair is a critical step for cancer development, if dysregulated. The replacement histone variant H2AX senses DNA double-strand breaks (DSBs), whereupon H2AX is rapidly phosphorylated at serine 139 (gH2AX). Through recruiting specific proteins/enzymes, gH2AX mediates post-DSB cell fate determination by either activating DSB repair in surviving cells or inducing apoptosis in irreparably damaged cells. To reveal exactly how the cell fate determining pathways are regulated or dysregulated by H2AX, we have been extending the uses of quantitative proteomics to screen the H2AX-interacting protein network (interactome) formed under different DSB-induced physiological conditions, which lead to systemic identifications of a number of novel tumor promoters and suppressors.
- Li Wang, Ling Xie, YuanYu Lee, Srinivas Ramachandran, Li Zhou, Zhen Yan, Krzysztof Krajewski, Feng Liu, Brian D. Strahl, Jian Jin, Nikolay V. Dokholyan, and Xian Chen* (2015) A non-canonical bromodomain module promotes DNA damage response and radioresistance through recognizing a radiation-inducible lysine acetylation. Chemistry & Biology (Cell Press), In press.
- Cui Liu, Yanbao Yu, Feng Liu, John A. Wrobel, Li Zhou, Xin Wei, Harsha P. Gunawardena, Jian Jin, andXian Chen* (2014) A novel chromatin-activity-based protein complex pull-down approach reveals a chromatin complexome for systems regulation of gene-specific silencing. Nature Communications, 5, 5733, DOI:10.1038/ncomms6733
- Ling Xie, Cui Liu, Li Wang, Harsha P. Gunawardena, Yanbao Yu, Ruyun Du, Debra J. Taxman, Penggao Dai, Zhen Yan, Jing Yu, Stephen P. Holly, Leslie V. Parise, Yisong Wan, Jenny P. Ting, and Xian Chen* (2013) Protein Phosphatase 2A Catalytic Subunit a (PP2Ac) Plays a MyD88-dependent, Central Role in the Gene-Specific Regulation of Endotoxin Tolerance (ET). Cell Reports, 3(3) 678-688.
- Siwei Tang, Huimin Bao, Yang Zhang, Jun Yao, Pengyuan Yang, and Xian Chen* (2013) “14-3-3ε Mediates the Cell Fate Decision-making Pathways in Response of Hepatocellular Carcinoma to Bleomycin-induced DNA Damage” PLoS One, 8(3), e55268.
- YuanYu Lee, YanBao Yu, Harsha P. Gunawardena, Ling Xie, and Xian Chen* (2012) BCLAF1 is a Radiation-induced H2AX-interacting Partner Involved in gH2AX-mediated Regulation of Apoptosis and DNA Repair, Cell Death & Disease (Nature Publishing Group), 3, e359.
- Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Röder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Falconnet E, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Ruan X, Hayashizaki Y, Harrow J, Gerstein M, Hubbard T, Reymond A, Antonarakis SE, Hannon G, Giddings MC, Ruan Y, Wold B, Carninci P, Guigó R, Gingeras TR. (2012) Landscape of transcription in human cells, Nature, 489, 101-108.
- Yu Lei, Haitao Wen,Yanbao Yu, Debra J. Taxman, Lu Zhang, Douglas G. Widman, Karen V. Swanson, Kwun-Wah Wen, Blossom A. Damania, Chris B. Moore, Patrick M. Giguère, David P. Siderovski, John Hiscott, Babak Razani, Clay F. Semenkovich, Xian Chen, and Jenny P.-Y. Ting (2012) NLRX1 and TUFM form a mitochondrial complex that regulates type 1 interferon and autophagy.Immunity, 36, 933-46.
- ENCODE Project Consortium, Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M. (2012) An Integrated Encyclopedia of DNA Elements in the Human Genome. Nature, 489, 57-74.
- Yanbao Yu, Ling Xie, Harsha P. Gunawardena, Jainab Khatun, Christopher Maier, Maarten Leerkes, Morgan Giddings, and Xian Chen* (2012) GOFASP: An Integrated Approach of GELFrEE, Optimized Digestion-assisted FASP for Efficient and Comprehensive Membrane Proteome Analysis. Anal. Chem, 84, 9008-9014.
- Harsha P. Gunawardena, Yi Huang, Haiyang Wang, Ling Xie, Ruyun Du, and Xian Chen (2011) Unambiguous Identification of Serine Phosphorylations of LRR Fli-I-interacting protein 2 involved in TLR4-Mediated Signaling. Journal of Biological Chemistry,286, 10897-10910.
- Shimin Zhao, Wei Xu, Wenqing Jiang, Wei Yu, Yan Lin, Tengfei Zhang, Jun Yao, Li Zhou, Hong Li, Yixue Li, Jiong Shi, Lunxiu Qin, Pengyuan Yang, Xian Chen, Qunying Lei, Kun-Liang Guan*, and Xue Xiong* (2010) Protein acetylation plays an extensive role in regulating cellular metabolism, Science, 327, 1000-1004.
- Ling Xie, Linhong Jing, Yanbao Yu, Kazuhiro Nakamura, Carol E. Parker, Gary L. Johnson, and Xian Chen* (2009) In vivo Profiling Endogenous Interactions with Knock-out (iPEIK), Anal Chem. 81 (4),1411–1417.
- Peigao Dai, Sun Young Yeong, Yanbo Yu, Weidong Wu, Taohua Leng, Ling Xie, and Xian Chen* (2009) Modulation of TLR Signaling by Multiple MyD88-Interacting Partners Including Leucine-Rich Repeat Fli-I-Interacting Proteins1, Journal of Immunology, 2009, 182, 3450-3460.
- Xian Chen*, Liwei Sun, Yubao Yu, Yue Yan, and Pengyuan Yang (2007) Amino Acid-coded Tagging-based Approaches in Quantitative Proteomics. Expert Review of Proteomics, 4:25-37.
- Tianyi Wang, Tapani Ronni, Sheng Gu, Susan Sun, Helen Yin, and Xian Chen* (2006) Fliih Negatively Modulates the MyD88-dependent Signaling Pathway. Journal of Immunology 176:1355-1362.
- Yu-Chun Du, Sheng Gu, Jian,hong Zhou, Tianyi Wang, Hong Cai, Mark A. MacInnes, E. Morton Bradbury, and Xian Chen* (2006) The Dynamic Alterations of H2AX Complex during DNA Repair Detected by a Proteomic Approach Reveal the Critical Roles of Ca2+/Calmodulin in the Ionizing Radiation-induced Cell Cycle Arrest. Mol. Cell. Proteomics, 5:1033-1044.
- Sheng Gu, Zhihe Liu, Songqin Pan, Zeyu Jiang, Huimei Lu, Or Amit,, Jian Yu, Chien-An A. Hu, Xian Chen* (2004) Global Investigation of p53-Induced Apoptosis Through Quantitative Profiling Regulatory Proteins Using Comparative Amino Acid-Coded Tagging Proteomics. Mol. Cell. Proteomics. 3(10)998-1008.