50 Undine Rd, Unit 3 Dana-Farber Cancer Institute, Harvard Medical School
Brighton, MA 02135 Smith 1156, 44 Binney St, Boston, MA 02115
Cell: 857-207-1295 Phone: 617-525-4449
Education and Training
07/2006 - Postdoctoral Research Fellow
Dana-Farber Cancer Institute & Brigham Women’s Hospital, Harvard Medical School
Advisors: Jarrod A. Marto, Chance John Luckey
06/2006 PhD Department of. Chemistry, University of Washington
Institute for Systems Biology, Seattle
Advisor: Rudolf F. Aebersold
06/2001 M.S. Fudan University, P.R. China. Advisor: Pengyuan Yang
06/1998 B.S. Fudan University, P.R. China. Advisor: Pengyuan Yang
Postdoctoral Research Accomplishments
Despite the clinical promise of ES cells and recent successes in generation of iPS cells from numerous, readily available differentiated cell types, we know surprisingly little about the molecular mechanisms by which pluripotent cells integrate internal and external cues during initiation and execution of differentiation programs. In particular, very little has been discovered about the primary or early molecular determinants that establish an appropriate molecular framework for exit of pluripotent cells from their self-renewing ground state. My postdoctoral research has focused on deciphering the signaling mechanisms in pluripotent stem cells using sensitive phosphoproteomics tools in addition to biochemical and genetic approaches.
1. Development of phosphoproteomic approaches to understand embryonic stem cell fate transition mechanism. (Ficarro*, Zhang*, Lu* (* equal contributions), et al, Analytical Chemistry, 2009.)
Studying signaling events in ES cells requires the use of highly sensitive phosphoproteomic methods. Immunoblots reveal that overall phosphotyrosine levels in mouse and human ES cells are significantly reduced compared to that found in typical tumor cell lines. Under typical LC-MS conditions, I detected very few tyrosine phosphorylated peptides from mouse ES cells. To address this limitation, I developed a novel technique for fabrication of miniaturized LC-electrospray assemblies and realized a 10-fold improvement in detection limit and dynamic range. This improvement enables phosphoproteomic analysis from only 105-106 mouse and human ES cells.
2. Development of comprehensive proteomics platform to characterize early-stage protein expression patterns during embryonic stem cell fate transition. (Zhou*, Lu* (* equal contributions), et al, Nature Communication, manuscript under revision and is available upon request.)
In stark contrast, systematic generation of protein-level data lags well-behind genomics in virtually every aspect: depth of coverage, throughput, ease of sample preparation, and overall experimental time. To bridge this gap I collaborated with other lab members to develop an approach that relies on (i) simple detergent lysis and single-enzyme digest, (ii) extreme, orthogonal separation of peptides, and (iii) true nanoflow LC-MS/MS that provides high peak capacity and ionization efficiency. This automated platform for deep efficient peptide sequencing and quantification (DEEP SEQ) mass spectrometry provides both genome-scale proteome coverage and accurate quantification based on multiplexed isotope labels. In a model of the early embryonic to epiblast transition in mouse embryonic stem cells, I unambiguously identified 11,352 gene products, including low-abundance transcriptional regulators that spanned 70% of Swiss-Prot, a scale equivalent to genome-wide RNA-Seq ribosomal profiling.
3. Signaling regulates alternative splicing and expression of specific epigenetic factors to form a feedback loop in support of self-renewal in pluripotent stem cells. (Lu, et al, manuscript currently under review at Cell Stem Cell and is available upon request.)
I applied the high-sensitivity phosphoproteomics tools to investigate the signaling pathways in human ES and induced-pluripotent stem (iPS) cells. In collaboration with Dr. George Daley’s laboratory, I used orthogonal measurements (microarray, proteomics, and phosphoproteomics) to define and interpret a molecular signature of pluripotency in the context of macromolecular networks and found that a subset of splicing factors consistently hyperphosphorylated across pluripotent cell populations, including SFRS2, RBM17, PRPF40A, and SRFS11, along with the splicing-related kinase CDK12, was required to maintain self-renewal in human ES cells. Furthermore, these proteins mediated cell type-specific splicing of the epigenetic factor MBD2. I further discovered that SFRS2, MBD2, and the pluripotency factors form a feedback loop to collectively support pluripotency maintenance. These results suggest that signaling pathways regulate the mRNA splicing machinery to generate specific gene isoforms that collectively may represent a largely unexplored set of self-renewal factors.
Earlier Research Experience
2001- 2006 Quantitative Proteomics Method Development and Applications
Absolute Quantification of Specific Proteins in Complex Mixtures. (Lu, et al, Analytical Chemistry, 2009)
Novel methodology utilizing VICAT (visible isotope-coded affinity tags) reagents and tandem mass spectrometry to quantify particular proteins of high biological interest in complex protein mixtures such as cell lysates and blood sera
Novel Method to Evaluate Potential Disease Markers in Blood Sera. (Lu, et al, Methods in Molecular Biology, 2006)
Application of the established VICAT method to investigate potential disease serum markers, as an economic and rapid alternative to the traditional ELISA assay
1997 – 2001 Analytical Instrumentation and Methodology Study
Pulse Electrospray Ionization Process: Instrumentation and Mechanism. (Lu, et al, Analytical Chemistry, 2001)
Application of Dual Electrospray Ion Sources to Improve Mass Accuracy in Mass Spectrometry Measurement. (Zhou, Shui, Lu, et al, Rapid Communication in Mass Spectrometry, 2002)
De-Novo Peptide Sequencing Using Correlation Method. (Song, Yue, Lu, et al, Chinese Journal of Chemistry, 2002)
Quantitative Electronic Nose for Alcohol Test. (Lu, et al, Analytica Chimica Acta, 2000)
American Chemical Society
American Society for Mass Spectrometry
International Society of Stem Cell Research
Society for Biological Engineers
Honors and Funding
2004 Young Investigator Award, Human Proteome Organization 2004, Beijing, China
2004 Student Fellowship, Methods in Protein Structure Analysis Conference 2004, Seattle, WA
2000 Star of Science Fellowship, Fudan University
2000 Fellowship, GE China
1999 Silver Award, 6th Challenge Cup Chinese National Colleges’ Contest in Scientific and Technological Research
1999 IET Scholarship
1998 Outstanding Student Award, Fudan University
1994-1998 People’s Scholarship, Fudan University
Yu Lu, Liping Bian, Pengyuan Yang. Quantitative artificial neural network for electronic noses. Analytica Chimica Acta, vol. 417, pp. 101-110, 2000.
Yu Lu, Liping Bian, Feng Zhou, Ping Sun, Pengyuan Yang, Yinlong Guo, Chongtian Yu. Preliminary research on pulsed-electrospray phenomenon. Chemical Journal of Chinese Universities, vol. 22, pp. 560-562, 2001.
Yu Lu, Feng Zhou, Wenqing Shui, Liping Bian, Pengyuan Yang. Pulsed electrospray for mass spectrometry. Analytical Chemistry, vol. 73, pp. 4748-4753, 2001.
Lijin Wen, Liping Bian, Yu Lu, Meizhuo Zhang, Liping Yu, and Pengyuan Yang. Electronic noses using quantitative artificial neural network. (2001) Chemical Research in Chinese Universities, 17, 380-386.
Feng Zhou, Wenqing Shui, Yu Lu, Pengyuan Yang, Yinlong Guo. High accuracy mass measurement of peptides with internal calibration using a dual electrospray ionization sprayer system for protein identification. Rapid Communications in Mass Spectrometry, vol. 16, pp. 505-511, 2002.
Junfei Wei, Wenqing Shui, Feng Zhou, Yu Lu, Kankai Chen, Guobing Xu, Pengyuan Yang. Naturally and externally pulsed electrospray. Mass Spectrometry Reviews, vol. 21, pp. 148-162, 2002.
Lijing Wen, Liangyi Zhang, Feng Zhou, Yu Lu, Pengyuan Yang. Quantitative determination of Freon gas using an electronic nose. Analyst, vol. 127, pp. 786-791, 2002.
Haowei Song, Guihua Yue, Yu Lu, Pengyuan Yang, Honghai Wang. Sequence pattern correlation of amino acid in collion-induced dissociation electrospray ionization mass spectrometry. Chinese Journal of Chemistry, vol. 20, pp. 467-473, 2002.
Liangyi Zhang, Lijin Wen, Yu Lu, and Pengyuan Yang. Quantitative fuzzy neural network for analytical determination. (2002) Analytica Chimica Acta, 468, 105-117.
Jeffery A. Ranish, Steven Hahn, Yu Lu, Eugene C. Yi, Xiao-Jun Li, Jimmy Eng, Ruedi Aebersold. Identification of TFB5, a new component of general transcription and DNA repair factor IIH. Nature Genetics, vol. 36, pp. 707-713, 2004.
Yu Lu, Patricia Bottari, Frantisek Turecek, Ruedi Aebersold, Michael H. Gelb. Absolute quantification of specific proteins in complex mixtures using visible isotope-coded tags. Analytical Chemistry, vol. 76, pp. 4104-4111, 2004.
Yu Lu, Michael H. Gelb, Frantisek Turecek, and Ruedi Aebersold. A novel method to quantify serum biomarkers via visible isotope-coded affinity tags and tandem mass Spectrometry. (2004) Molecular & Cellular Proteomics, 3, S132-S132.
Yu Lu, Patricia Bottari, Ruedi Aebersold, Frantisek Turecek; Michael H. Gelb. Absolute Quantification of Specific Proteins in Complex Mixtures Using Visible Isotope-Coded Affinity Tags (VICAT Reagents). Chapter for Recent Developments in Quantitative Proteomics, Methods in Molecular Biology, Secchi, S., Ed. (2006).
Yu Lu, Patricia Bottari, Ruedi Aebersold, Frantisek Turecek, Michael H. Gelb. Absolute quantification of specific proteins in complex mixtures using visible isotope-coded tags. Methods in Molecular Biology, vol. 359, pp. 159-176, 2007.
Scott B. Ficarro, Yi Zhang, Yu Lu, Ahmadali R. moghimi, Manor Askenazi, Elzbieta Hyatt, Eric D. Smith, Leah Boyer, Thorsten Schlaeger, C. John Luckey, Jarrod A. Marto. Improved electrospray ionization efficiency compensates for diminished chromatographic resolution and enables proteomics analysis of tyrosine signaling in embryonic stem cells. Analytical Chemistry, 81, 3440-3447, 2009
C. John Luckey, Yu Lu, Jarrod A. Marto. Understanding the first steps in embryonic stem cell exit from the pluripotent state. Transfusion, 51, 118S-124S, 2011.
Amy Brock, Hui-Tong Goh, Binxia Yang, Yu Lu, Hu Li, Yuin-Han Loh. Cellular reprogramming: a new technology frontier in pharmaceutical research. Pharmaceutical Research, 29, 35-52, 2012.
Feng Zhou, Yu Lu, Scott B. Ficarro, James Webber, Jarrod A. Marto. A Nanoflow Low Pressure High Peak Capacity Single Dimension LC-MS/MS Platform for In-Depth Analysis of Mammalian Proteomes. Analytical Chemistry, 84, 5133-5139, 2012.