Our primary interest is to elucidate the structure of all functional DNA elements in the human genome with a focus on the transcriptome and transcriptional regulation. Our strategies include the development of innovative cloning and sequencing technologies to address questions pertinent to human disease. To this end, we concentrate on cancer genomics, stem cells biology, and in characterizing the metagenome of the microbial populations involved in human biology.

One of our main research focuses is to continually innovate highly efficient and accurate tag-based DNA sequencing and mapping methodologies for transcriptome and genome analysis. In this effort, we first developed 5'LongSAGE and 3'LongSAGE protocols to map transcription start sites (TSS) and polyadenylation sites (PAS) of genes (Wei et al. 2004 PNAS). With this new capability, we devised the paired-end ditagging (PET) strategy and developed the Gene Identification Signature (GIS) analysis to precisely demarcate the boundaries of full-length transcripts (Ng et al. 2005 Nature Methods). GIS analysis is proved to be 30 folds more efficient than conventional sequencing approaches for transcripts annotation, and possesses a unique capability to identify unconventional transcripts derived from trans-splicing and chromosomal rearrangements.

Immediately afterward, we invented the ChIPPET analysis (chromatin immuno-precipitation coupled with paired-end ditagging) for highly accurate, robust and unbiased genome-wide identification of transcription factor binding sites. Using ChIP-PET, we mapped the global p53 binding sites in the human genome of colon cancer cells and identified large numbers of novel p53 target genes (Wei et al. 2006 Cell). To further push the envelop, we adapted the new 454 sequencing method and developed the multiplex sequencing for paired-end ditag (MS-PET) analysis (Ng et al. 2006 Nucleic Acid Research), which achieved another 100-fold efficiency improvement compared to the use of conventional sequencing method for PET experiments. To accommodate and streamline the analysis of large volumes of PET sequences, in collaboration with Dr Wing-Kin Sung and his team, we developed an ultra-fast tag-to-genome mapping algorithm (SAT2G) and a complete computational program suite, PET-Tool, (Chiu et al. 2006 BMC Bioinformatics) for PTE data processing and management. We have also developed, in collaboration with Dr Atif Shahab and his team of BII (Singapore Bioinformatics group), the tag-to-genome web browser (T2G) to display and deliver the PET analyses results to end users. These are now back-bone technologies for the institute's biological programs.

Continuing the theme of developing technologies to understand human disease, we have pursued the discovery of uncharacterized pathogens relevant to human health. During the SARS outbreak, we decoded the genome of SARS coronal virus and identified sequence variations that linked to SARS origins (Ruan et al. Lancet 2003). Extending this discovery approach, we have established a unique metagenomic analysis capability that uses shotgun sequencing and genome sequence assembly techniques to uncover community microbial genomes from uncultured microbes concentrated by tangential filtration. We have been applying this metagenomic approach to characterize viral and bacteria flora in human gastrointestinal tracts. One of the surprising discoveries found in this endeavor was that life plant viruses were found prevalent in the human guts, and that plant viruses might use humans as vehicle for dissemination (Zhang et al. 2006 PLoS Biology).

With the establishment of integrated high throughput and high precision technology platform, we are poised to address complex biological questions such as how cancer cells progress, how stem cells maintain their unique pluripotent properties, and how unknown infectious agents interact with hosts. We have cultivated tight collaborative relationships with cancer and stem cell biology groups within GIS and across the world. These collaborations are starting to yield exciting results (Wei et al. 2005 Stem Cells; Loh et al. 2006 Nature Genetics; Zeller et al. 2006 PNAS).



Key Representative Publications

Kuo Ping Chiu, Chee-Hong Wong, Qiong Yu Chen, Chia Lin Wei, Wing-Kin Sung, and Yijun Ruan (2006) "PET-Tool: A Software Suite for Comprehensive Processing and Managing of Paired-End diTag Sequence Data" BMC Bioinformatics 7:390 (doi:10.1186/1471-2105-7-390).

Karen I. Zeller, XiaoDong Zhao, Charlie W. H. Lee, Kuo Ping Chiu, Hong Sain Ooi, Fei Yao, Atif Shahab, How Choong Yong, YuTao Fu, Zhiping Weng, Vladimir A. Kuznetsov, Wing-Kin Sung, Yijun Ruan, Chi V.Dang, and Chia-Lin Wei (2006) "Global Mapping of c-Myc Binding Sites and Target Gene Networks in Human B Cells" PNAS (in press).

Zhang T, Breitbart M, Lee W.H, Run J.Q, Wei C.L, Soh S.W, Hibberd M.L, Liu E.T, Rohwer F and Ruan Y "RNA viral community in human feces: prevalence of plant pathogenic viruses" PLoS Biology 4:e3, 2006.

Wei C.L, Wu Q, Vega V.B, Chiu K.P, Ng P, Zhang T, Shahab A, Ridwan A, Fu Y.T, Weng Z, Lee Y.L, Liu J.J, Kuznetsov V.A, Sung K, Lim B, Liu E.T, Yu Q, Ng H.H and Ruan Y "A Global Mapping of p53 Transcription Factor Binding Sites in the Human Genome" Cell 124:207-219, 2006.

Ng P, Tan J.S, Chiu K.P, Ooi H.S, Lee Y.L, Fullwoods M.J, Du L, Sung K, Wei C.L and Ruan Y "Multiplex Sequencing of Paired-End diTag for Human Transcriptome and Genome Characterization" Nucleic Acid Research (in press), 2006.

Loh Y.H, Wu Q, Chew J.L, Vega V.B, Zhang W, Chen X, Bourque G, George J, Leong B, Liu J, Wong K.Y, Sung K, Lipovich L, Kuznetsov V.A, Robson P, Stanton L.W, Wei C.L, Ruan Y, Lim B, Ng H.H "The Oct4 and Nanog transcription network that regulates pluripotency in mouse embryonic stem cells" Nature Genetics 38:431-440, 2006.

Ng P, Wei C.L, Sung K, Chiu K.P, Lipovich L, Ang C.C, Gupta S, Shahab A, Ridwan A, Wang C.H, Liu E.T and Ruan Y "Gene Identification Signature (GIS) analysis for transcriptome analysis and genome annotation" Nature Method 2:105-111, 2005.

Wei C.L, Ng P, Chiu K.P, Wong C.H, Ang C.C, Lipovich L, Liu E.T and Ruan Y "5' Long serial analysis of gene expression (LongSAGE) and 3' LongSAGE for transcriptome characterization and genome annotation" PNAS 101:11701-11706, 2004.

Ruan Y, Wei C.L, Ee A.L, Vega V.B, Thoreau H, Su S.T, Chia J.M, Ng P, Chiu K.P, Lim L, Zhang T, Peng C.K, Lin E.O, Lee N.M, Yee S.L, Ng L.F, Chee R.E, Stanton L.W, Long P.M and Liu E.T "Comparative full-length genome sequence analysis of 14 SARS coronavirus isolates and common mutations associated with putative origins of infection" Lancet 361:1779-1785, 2003.