Senior Group Leader, Genome Institute of Singapore
Associate Professor of Medicine, Harvard Medical School
Associate Physician, Beth Israel Hospital, Harvard Medical School
RESEARCH FOCUS
ES cell as an engine for Pluripotency, Tissue Regeneration and Epigenomic alteration
ES cells hold great promises for cell therapeutics. The focus of our team is to elucidate 3 fundamental paradigm underlying the basis for the practical exploitation of ES cells, combining a gene discovery effort with gene functionalization studies.
A. Gene Discovery
Pluripotency
ES cells are totipotent. Currently only a handful of pluripotency -associated genes are being studied. We want to know what is the scope of genetic factors and networks harnessed by ES cells to confer this pluripotent state. The answers will guide better ways to grow and manipulate ES and other stem cells . We follow two research program using both murine and human ES cells.
Identification of regulatory genes by transcriptome analysis of ES cells and ES cells undergoing differentiation under various conditions using a number of techniques including microarray profiling, massively parallel sequential sequencing (MPSS) and EST data base mining and bioinformatics tool.
Investigation of an emerging class of regulatory micro-RNAs (miRNAs) that perform important function in development and differentiation by blocking translation or degrading target mRNAS. We utilize both publicly available data base and our own gene discovery effort to identify those miRNAs that are specific to ES cells and other somatic progenitor cells. Projects in the lab are aimed at discovering the function of these miRNAs and their target RNAs
Differentiation
Why do ES cells differentiate spontaneously into many tissues? This question is tied in with the enquiry into pluripotency. Therefore the kinetics of transcriptome profile during ES differentiation also identify candidate genes associated with early differentiation and we ask the question what is the connection between genes maintaining pluripotency and genes inhibiting differentiation? Do miRNAs play a role in modulating other genes in orchestrating ES cell differentiation? In collaboration with other members of the Stem Cell group we are also testing and identifying genes driving the more specific differentiation into mesodermal and endodermal tissues.
Reprogramming
The ability of somatic nuclei to be reprogrammed in oocytes or cells to undergo lineage
switch points to the malleability of the genome. The reprogramming of somatic cells after fusion with ES cells showed that the intracellular environment of ES cells has the unique capability of altering epigenetically other nuclei. Thus ES cell may be used as a surrogate system to probe into the molecular basis of reprogramming. We are developing ES-cell assay system to evaluate and quantify reprogramming of other cells and then to use these assays to test and identify genes that have epigenetic function. This effort is link to other efforts in the Stem Cell group to capture the transcriptome of the oocyte.
B. Gene function
A large list of transcripts, including novel coding and non-coding genes, have been discovered thus far by the combined effort of the Stem Cell group. To validate and evaluate the significance of these genes , we are developing platforms for gene functionalization utilizing technologies that include gene knock-down by RNAi, anti-sense oligonucleotides, over-expression by constitutive and inducible expression vectors. In selected cases, functional studies are taken forward to in vivo studies in animal models.
M.D., University of Western Ontario, Ontario, Canada
1986
Ph.D., University of Western Ontario, Ontario, Canada
Postdoctoral Training
Internship and Residencies:
1974-1975
Resident in Medicine, McMaster University, Hamilton, Canada
1975
Resident in General Surgery, McMaster University, Hamilton, Canada
1976-1977
Medical Officer, Queen Elizabeth Hospital, Sabah, Malaysia
1977-1979
Resident in Medicine, University of Western Ontario, Ontario, Canada
1979-1981
Fellow in Hematology/Oncology, Princess Margaret Hospital, University of Toronto, Canada
Clinical and Research Fellowships:
1981-1985
Ph.D. Program, Princess Margaret Hospital, University of Toronto, Institute of Medical Science
1985-1988
Post-doctoral Research Fellow, Childrens Hospital, Harvard Medical School, Boston, MA
Licensure and Certification:
1980
American Board of Internal Medicine
1980
F.R.C.P. (C) Fellow of Royal College of Physicians
PROFESSIONAL APPOINTMENTS
Academic Appointments
1988-1993
Instructor in Medicine, Harvard Medical School.
1993-1997
Assistant Professor of Medicine, Harvard Medical School
1998-
Associate Professor of Medicine, Harvard Medical School
2002-
Senior Group Leader, Genome Institute of Singapore
Hospital Appointments
1998-
Associate Physician, Beth Israel Hospital, Harvard Medical School
HONORS AND AWARDS
1993-1998
Scholar of the Leukemia Society of America
1987-1988
Howard Hughes Postdoctoral Fellowship
1985-1987
M.R.C. Fellowship (Postdoctoral)
1981-1985
M.R.C. Fellowship (Ph.D.)
1974
Charles E. Frost Medal and Award (for clinical therapeutics and medicine)
1973
Alpha Omega Alpha
1969
William Wyatt Scholarship (for best undergraduate entering honors course)
1968-1974
Dean's Honors List (Every year)
1968-1974
Colombo Plan Scholarship (Medicine)
COMMITTEE AND ADVISORY BOARD
National and Regional
1995-2000
HEM-2 Study Section; Member of Ad Hoc Grant review Comitee for National Institute of Health, U.S.A.
2003-
Blood Development Study Section Ad Hoc Grant review, NIH, U.S.A.
1994-1996
Drug, Hematology and Pharmacology Study Section; Member of Grant Review Committee for American Cancer Society.
1997-
Leukemia and Blood Development Study Section; Member of Grant Reviw Committee, American Cancer Society
1998-2004
Editorial Board. BLOOD Journal
2004-
Grant Review Committee, Basic Science Section, BMRC, Singapore
International
1994-
Ad Hoc External Reviewer for Canadian Red Corss Reviewer Grants
1996-
Ad Hoc External Reviewer, International Human Frontier Science Program
1998-
External Reviewer, Italian University Grants Warrant Committee
2004
Steering Committee Member, International Regulome Consortium
SELECTED PUBLICATIONS
1. Tay Yvonne M-S, Tam Wai-Leong, Ang Yen-Sin, Gaughwin Philip M, Yang Henry, Wang Weijia, Liu Rubing, George Joshy, Ng Huck-Hui, Perera Ranjan J, Lufkin Thomas, Rigoutsos Isidore, Thomson Andrew M, Lim Bing "MicroRNA-134 modulates the differentiation of mouse embryonic stem cells, where it causes post-transcriptional attenuation of Nanog and LRH1." Stem Cells 2008 Jan ; 26(1) : 17-29 Abstract
2. Tam Wai-Leong, Lim Chin Yan, Han Jianyong, Zhang Jinqiu, Ang Yen-Sin, Ng Huck-Hui, Yang Henry, Lim Bing "T-cell factor 3 regulates embryonic stem cell pluripotency and self-renewal by the transcriptional control of multiple lineage pathways." Stem Cells 2008 Aug ; 26(8) : 2019-31 Abstract
3. Tay Yvonne, Zhang Jinqiu, Thomson Andrew M, Lim Bing*, Rigoutsos Isidore* [* Co-Senior Authors] "MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation." Nature 2008 Sep 17 ; : Abstract
4. Lim Chin Ya n, Tam Wai-Leong, Zhang Jinqiu, Ang Haw Siang, Jia Hui, Lipovich Leonard, Ng Huck-Hui, Wei Chia-Lin, Sung Wing Kin, Robson Paul, Yang Henry, Lim Bing "Sall4 Regulates Distinct Transcription Circuitries in Different Blastocyst-Derived Stem Cell Lineages." Cell Stem Cell 2008 Sep 17 ; : Abstract
5. Soh Boon Seng, Song Chun Meng, Vallier Ludovic, Li Pin, Choong Cleo, Yeo Boon Huat, Lim Elaine Hsuen, Pedersen Roger A, Yang Henry He, Rao Mahendra, Lim Bing "Pleiotrophin enhances clonal growth and long-term expansion of human embryonic stem cells." Stem Cells 2007 Dec ; 25(12) : 3029-37 Abstract
6. Zhang Jinqiu, Tam Wai-Leong, Tong Guo Qing, Wu Qiang, Chan Hsiao-Yun, Soh Boon-Seng, Lou Yuefei, Yang Jianchang, Ma Yupo, Chai Li, Ng Huck-Hui, Lufkin Thomas, Robson Paul, Lim Bing "Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1." Nat. Cell Biol. 2006 Oct ; 8(10) : 1114-23 Abstract
7. Miranda Kevin C, Huynh Tien, Tay Yvonne, Ang Yen-Sin, Tam Wai-Leong, Thomson Andrew M, Lim Bing*, Rigoutsos Isidore* "A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes." Cell 2006 Sep 22 ; 126(6) : 1203-17 [Co-Senior Authors] Abstract
8. Kocabas Arif Murat, Crosby Javier, Ross Pablo J, Otu Hasan H, Beyhan Zeki, Can Handan, Tam Wai-Leong, Rosa Guilherme J M, Halgren Robert G, Lim Bing*, Fernandez Emilio*, Cibelli Jose Bernardo* "The transcriptome of human oocytes." Proc. Natl. Acad. Sci. U.S.A. 2006 Sep 19 ; 103(38) : 14027-32 Abstract
9. Loh Yuin-Han, Wu Qiang, Chew Joon-Lin, Vega Vinsensius B, Zhang Weiwei, Chen Xi, Bourque Guillaume, George Joshy, Leong Bernard, Liu Jun, Wong Kee-Yew, Sung Ken W, Lee Charlie W H, Zhao Xiao-Dong, Chiu Kuo-Ping, Lipovich Leonard, Kuznetsov Vladimir A, Robson Paul, Stanton Lawrence W, Wei Chia-Lin, Ruan Yijun, Lim Bing, Ng Huck-Hui "The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells." Nat. Genet. 2006 Apr ; 38(4) : 431-40 Abstract
10. Nicolas O. Fortunel, Hasan Otu, Huck Hui NG, Chen, J., Mu, X., Chevassut, T., Li, X., Joseph M., Bailey C., Hatzfeld, J., Usta, F., Vinsensius Berlian VEGA, Long M. Philip, Towia Liberman, T., Bing LIM (2003) "Comment on `Stemness: Transcriptional Profiling of Embryonic and Adult Stem Cells' and `A Stem Cell Molecular Signature'" Science 302 393
