Gene regulation

Participants: Zhizhuo Zhang, Vipin, Guoliang Li, Wing-Kin Sung

Background

The process of controlling the expression of genes is known as gene regulation. Gene regulation dictates when, where (in what tissue(s)), and how much of a particular protein is produced. This decides the development of cells and their responses to external stimuli. The most direct control mechanism is transcription regulation, which controls whether the transcription process of a gene should be initiated. In eukaryotic cells, RNA-polymerase II is responsible for the transcription process. However, it is incapable of initiating transcription on its own. It does so with the assistance of a number of DNA-binding proteins called transcription factors (TFs). TFs bind the DNA sequence and interact to form a pre-initiation complex (PIC). RNA-polymerase II is recruited in the PIC, and then the transcription begins. The crucial point of the regulation mechanism is the binding of TFs to DNA. Disruptions in gene regulation are often linked to a failure of TF binding, either due to mutation of the DNA binding site, or due to mutation of the TF itself.

Due to the advance of next generation sequencing, a number of techniques have been developed for studying gene regulation. They include ChIP-seq, ChIA-PET, Hi-C, etc.

Objectives

In this project, we will develop computational tools for analyzing the next generation sequencing data. We also will collaborate with biologists to make new biological discovery. More precisely, we have the following subprojects.

• Peak calling and Interaction Finding: Peak calling is a computational method that identify genomic regions which are rich in ChIP-seq reads. They allow us to find the binding sites of different transcription factors and identify histone modification regions. We developed CCAT for calling peaks from ChIP-seq data. We also developed ChIA-PET tool, which allows us to predict the interaction of genomic regions from ChIA-PET datasets. From the interaction data, we further develop a tool ChromSDE to predict the 3D chromatin structure of our genome.
• Motif finding: The binding sites of some transcription factors are sequence specific. Given a list of binding sites, we can computationally predict such specific sequence, which is called motifs. We developed two motif finding tools, which are localmotif, CENTDIST and SEME.
• Collaborate with biologists: By using the tools developed by the team, we also help our collaborators to analyze ChIP-seq and ChIA-PET data.

Software

• CWig: Compressed representation of Wiggle/BedGraph format
• CCAT: A ChIP-seq peak caller
• CENTDIST: A motif scanner for ChIP-seq data
• SEME: A de novo motif finder for ChIP-seq data
• ChIA-PET Tool
• ChromSDE: Inference of Spatial Organizations of Chromosomes Using Semi-definite Embedding Approach and Hi-C Data

Selected Publications

• Hoang, D. H. and Sung, W.-K. CWig: Compressed representation of Wiggle/BedGraph format. Bioinformatics, 2014.
• Lam, S. H., Lui, E. Y., Li, Z., Cai, S., Sung, W.-K., Mathavan, S., Lam, T. J. and Ip, Y. K. Differential transcriptomic analyses revealed genes and signaling pathways involved in iono-osmoregulation and cellular remodeling in the gills of euryhaline Mozambique tilapia, Oreochromis mossambicus. BMC Genomics, Vol. 15, pp. 921, 2014.
• Koe, C. T., Li, S., Rossi, F., Wong, J. J. L., Wang, Y., Zhang, Z., Chen, K., Aw, S. S., Richardson, H. E., Robson, P., Sung, W.-K., Yu, F., Gonzalez, C. and Wang, H. The Brm-HDAC3-Erm repressor complex suppresses dedifferentiation in Drosophila type II neuroblast lineages. Elife, Vol. 3, pp. e01906, 2014.
• Zhang, Z., Chang, C. W., Hugo, W., Cheung, E. and Sung, W.-K. Simultaneously learning DNA motif along with its position and sequence rank preferences through expectation maximization algorithm. J Comput Biol, Vol. 20(3), pp. 237-248, 2013.
• Zhang, Z., Li, G., Toh, K.-C. and Sung, W.-K. 3D Chromosome Modeling with Semi-Definite Programming and Hi-C Data. J Comput Biol, Vol. 20(11), pp. 831-846, 2013.
• Zhang, J., Poh, H. M., Peh, S. Q., Sia, Y. Y., Li, G., Mulawadi, F. H., Goh, Y., Fullwood, M. J., Sung, W.-K., Ruan, X. and Ruan, Y. ChIA-PET analysis of transcriptional chromatin interactions. Methods, 2012.
• Heisig, J., Weber, D., Englberger, E., Winkler, A., Kneitz, S., Sung, W.-K., Wolf, E., Eilers, M., Wei, C.-L. and Gessler, M. Target Gene Analysis by Microarrays and Chromatin Immunoprecipitation Identifies HEY Proteins as Highly Redundant bHLH Repressors. PLoS Genet, Vol. 8(5), pp. e1002728, 2012.
• Li, G., Ruan, X., Auerbach, R. K., Sandhu, K. S., Zheng, M., Wang, P., Poh, H. M., Goh, Y., Lim, J., Zhang, J., Sim, H. S., Peh, S. Q., Mulawadi, F. H., Ong, C. T., Orlov, Y. L., Hong, S., Zhang, Z., Landt, S., Raha, D., Euskirchen, G., Wei, C.-L., Ge, W., Wang, H., Davis, C., Fisher-Aylor, K. I., Mortazavi, A., Gerstein, M., Gingeras, T., Wold, B., Sun, Y., Fullwood, M. J., Cheung, E., Liu, E., Sung, W.-K., Snyder, M. and Ruan, Y. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell, Vol. 148(1-2), pp. 84-98, 2012.
• Perna, D., Fagà, G., Verrecchia, A., Gorski, M. M., Barozzi, I., Narang, V., Khng, J., Lim, K. C., Sung, W.-K., Sanges, R., Stupka, E., Oskarsson, T., Trumpp, A., Wei, C.-L., Müller, H. and Amati, B. Genome-wide mapping of Myc binding and gene regulation in serum-stimulated fibroblasts. Oncogene, Vol. 31(13), pp. 1695-1709, 2012.
• Sandhu, K. S., Li, G., Poh, H. M., Quek, Y. L. K., Sia, Y. Y., Peh, S. Q., Mulawadi, F. H., Lim, J., Sikic, M., Menghi, F., Thalamuthu, A., Sung, W. K., Ruan, X., Fullwood, M. J., Liu, E., Csermely, P. and Ruan, Y. Large-scale functional organization of long-range chromatin interaction networks. Cell Rep, Vol. 2(5), pp. 1207-1219, 2012.
• Tan, P. Y., Chang, C. W., Chng, K. R., Wansa, K. D. S. A., Sung, W.-K. and Cheung, E. Integration of Regulatory Networks by NKX3-1 Promotes Androgen-Dependent Prostate Cancer Survival. Mol Cell Biol, Vol. 32(2), pp. 399-414, 2012.
• Tan, S. K., Lin, Z. H., Chang, C. W., Varang, V., Chng, K. R., Pan, Y. F., Yong, E. L., Sung, W. K. and Cheung, E. AP-2α regulates oestrogen receptor-mediated long-range chromatin interaction and gene transcription. EMBO J, Vol. 30(13), pp. 2750, 2011.
• Sandhu, K. S., Li, G., Sung, W.-K. and Ruan, Y. Chromatin interaction networks and higher order architectures of eukaryotic genomes. J Cell Biochem, 2011.
• Kong, S. L., Li, G., Loh, S. L., Sung, W.-K. and Liu, E. T. Cellular reprogramming by the conjoint action of ERα, FOXA1, and GATA3 to a ligand-inducible growth state. Mol Syst Biol, Vol. 7, pp. 526, 2011.
• Zhang, Z., Chang, C. W., Goh, W. L., Sung, W.-K. and Cheung, E. CENTDIST: discovery of co-associated factors by motif distribution. Nucleic Acids Res, 2011.
• Handoko, L., Xu, H., Li, G., Ngan, C. Y., Chew, E., Schnapp, M., Lee, C. W. H., Ye, C., Ping, J. L. H., Mulawadi, F., Wong, E., Sheng, J., Zhang, Y., Poh, T., Chan, C. S., Kunarso, G., Shahab, A., Bourque, G., Cacheux-Rataboul, V., Sung, W.-K., Ruan, Y. and Wei, C.-L. CTCF-mediated functional chromatin interactome in pluripotent cells. Nat Genet, 2011.
• Xu, H., Handoko, L., Wei, X., Ye, C., Sheng, J., Wei, C.-L., Lin, F. and Sung, W.-K. A Signal-Noise Model for Significance Analysis of ChIP-seq with Negative Control. Bioinformatics, Vol. 26(9), pp. 1199-1204, 2010.
• Laurent, L., Wong, E., Li, G., Huynh, T., Tsirigos, A., Ong, C. T., Low, H. M., Sung, K. W. K., Rigoutsos, I., Loring, J. and Wei, C.-L. Dynamic changes in the human methylome during differentiation. Genome Res, Vol. 20(3), pp. 320-331, 2010.
• Li, G., Fullwood, M. J., Xu, H., Mulawadi, F. H., Velkov, S., Vega, V., Ariyaratne, P. N., Mohamed, Y. B., Ooi, H.-S., Tennakoon, C., Wei, C.-L., Ruan, Y. and Sung, W.-K. ChIA-PET tool for comprehensive chromatin interaction analysis with paired-end tag sequencing. Genome Biol, Vol. 11(2), pp. R22, 2010.
• Narang, V., Mittal, A. and Sung, W.-K. Localized Motif Discovery in Gene Regulatory Sequences. Bioinformatics, Vol. 26(9), pp. 1152-1159, 2010.
• Fullwood, M. J., Liu, M. H., Pan, Y. F., Liu, J., Xu, H., Mohamed, Y. B., Orlov, Y. L., Velkov, S., Ho, A., Mei, P. H., Chew, E. G. Y., Huang, P. Y. H., Welboren, W.-J., Han, Y., Ooi, H. S., Ariyaratne, P. N., Vega, V. B., Luo, Y., Tan, P. Y., Choy, P. Y., Wansa, K. D. S. A., Zhao, B., Lim, K. S., Leow, S. C., Yow, J. S., Joseph, R., Li, H., Desai, K. V., Thomsen, J. S., Lee, Y. K., Karuturi, R. K. M., Herve, T., Bourque, G., Stunnenberg, H. G., Ruan, X., Cacheux-Rataboul, V., Sung, W.-K., Liu, E. T., Wei, C.-L., Cheung, E. and Ruan, Y. An oestrogen-receptor-alpha-bound human chromatin interactome. Nature, Vol. 462(7269), pp. 58-64, 2009.
• Santa, F. D., Narang, V., Yap, Z. H., Tusi, B. K., Burgold, T., Austenaa, L., Bucci, G., Caganova, M., Notarbartolo, S., Casola, S., Testa, G., Sung, W.-K., Wei, C.-L. and Natoli, G. Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J, Vol. 28(21), pp. 3341-3352, 2009.
• Sung, W.-K., Lu, Y., Lee, C. W. H., Zhang, D., Ronaghi, M. and Lee, C. G. L. Deregulated direct targets of the hepatitis B virus (HBV) protein, HBx, identified through chromatin immunoprecipitation and expression microarray profiling. J Biol Chem, Vol. 284(33), pp. 21941-21954, 2009.
• Vega, V. B., Cheung, E., Palanisamy, N. and Sung, W.-K. Inherent signals in sequencing-based Chromatin-ImmunoPrecipitation control libraries. PLoS One, Vol. 4(4), pp. e5241, 2009.
• Xu, H., Wei, C.-L., Lin, F. and Sung, W.-K. An HMM approach to genome-wide identification of differential histone modification sites from ChIP-seq data. Bioinformatics, Vol. 24(20), pp. 2344-2349, 2008.
• Wijaya, E., Yiu, S.-M., Son, N. T., Kanagasabai, R. and Sung, W.-K. MotifVoter: a novel ensemble method for fine-grained integration of generic motif finders. Bioinformatics, Vol. 24(20), pp. 2288-2295, 2008.
• Chen, X., Xu, H., Yuan, P., Fang, F., Huss, M., Vega, V. B., Wong, E., Orlov, Y. L., Zhang, W., Jiang, J., Loh, Y.-H., Yeo, H. C., Yeo, Z. X., Narang, V., Govindarajan, K. R., Leong, B., Shahab, A., Ruan, Y., Bourque, G., Sung, W.-K., Clarke, N. D., Wei, C.-L. and Ng, H.-H. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell, Vol. 133(6), pp. 1106-1117, 2008.
• Lim, C. Y., Tam, W.-L., Zhang, J., Ang, H. S., Jia, H., Lipovich, L., Ng, H.-H., Wei, C.-L., Sung, W. K., Robson, P., Yang, H. and Lim, B. Sall4 regulates distinct transcription circuitries in different blastocyst-derived stem cell lineages. Cell Stem Cell, Vol. 3(5), pp. 543-554, 2008.
• Wijaya, E., Rajaraman, K., Yiu, S.-M. and Sung, W.-K. Detection of generic spaced motifs using submotif pattern mining. Bioinformatics, Vol. 23(12), pp. 1476-1485, 2007.
• Lim, C.-A., Yao, F., Wong, J. J.-Y., George, J., Xu, H., Chiu, K. P., Sung, W.-K., Lipovich, L., Vega, V. B., Chen, J., Shahab, A., Zhao, X. D., Hibberd, M., Wei, C.-L., Lim, B., Ng, H.-H., Ruan, Y. and Chin, K.-C. Genome-wide mapping of RELA(p65) binding identifies E2F1 as a transcriptional activator recruited by NF-kappaB upon TLR4 activation. Mol Cell, Vol. 27(4), pp. 622-635, 2007.
• Zhao, X. D., Han, X., Chew, J. L., Liu, J., Chiu, K. P., Choo, A., Orlov, Y. L., Sung, W.-K., Shahab, A., Kuznetsov, V. A., Bourque, G., Oh, S., Ruan, Y., Ng, H.-H. and Wei, C.-L. Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell Stem Cell, Vol. 1(3), pp. 286-298, 2007.
• Chiu, K. P., Ariyaratne, P., Xu, H., Tan, A., Ng, P., Liu, E. T.-B., Ruan, Y., Wei, C.-L. and Sung, W.-K. K. Pathway aberrations of murine melanoma cells observed in Paired-End diTag transcriptomes. BMC Cancer, Vol. 7, pp. 109, 2007.
• Vega, V. B., Lin, C.-Y., Lai, K. S., Kong, S. L., Xie, M., Su, X., Teh, H. F., Thomsen, J. S., Yeo, A. L., Sung, W. K., Bourque, G. and Liu, E. T. Multiplatform genome-wide identification and modeling of functional human estrogen receptor binding sites. Genome Biol, Vol. 7(9), pp. R82, 2006.
• Wei, C.-L., Wu, Q., Vega, V. B., Chiu, K. P., Ng, P., Zhang, T., Shahab, A., Yong, H. C., Fu, Y., Weng, Z., Liu, J., Zhao, X. D., Chew, J.-L., Lee, Y. L., Kuznetsov, V. A., Sung, W.-K., Miller, L. D., Lim, B., Liu, E. T., Yu, Q., Ng, H.-H. and Ruan, Y. A global map of p53 transcription-factor binding sites in the human genome. Cell, Vol. 124(1), pp. 207-219, 2006.
• Chiu, K. P., Wong, C.-H., Chen, Q., Ariyaratne, P., Ooi, H. S., Wei, C.-L., Sung, W.-K. K. and Ruan, Y. PET-Tool: a software suite for comprehensive processing and managing of Paired-End diTag (PET) sequence data. BMC Bioinformatics, Vol. 7, pp. 390, 2006.
• Zeller, K. I., Zhao, X., Lee, C. W. H., Chiu, K. P., Yao, F., Yustein, J. T., Ooi, H. S., Orlov, Y. L., Shahab, A., Yong, H. C., Fu, Y., Weng, Z., Kuznetsov, V. A., Sung, W.-K., Ruan, Y., Dang, C. V. and Wei, C.-L. Global mapping of c-Myc binding sites and target gene networks in human B cells. Proc Natl Acad Sci U S A, Vol. 103(47), pp. 17834-17839, 2006.
• Ng, P., Wei, C.-L., Sung, W.-K., Chiu, K. P., Lipovich, L., Ang, C. C., Gupta, S., Shahab, A., Ridwan, A., Wong, C. H., Liu, E. T. and Ruan, Y. Gene identification signature (GIS) analysis for transcriptome characterization and genome annotation. Nat Methods, Vol. 2(2), pp. 105-111, 2005.