firstname.lastname@example.orgGrowth, Development and Metabolism Programme
Senior Principal Investigator
There is increasing evidence that the etiology of human metabolic diseases may have its origin in epigenetic misprogramming during early development, which is largely influenced by external factors such as maternal nutrition and other in utero conditions. This involves the interplay between DNA encoded genetic information and the epigenome comprising DNA sequence-independent factors such as CpG methylation pattern, posttranslational histone modifications, and miRNA expression, as well as their complex interactions in a spatiotemporal manner. In close collaboration with the bioinformatics team at SICS, our group studies epigenetic pathways by applying multiplexed and array based assay technologies to measure gene expression and DNA methylation in clinical specimens. In particular, we are interested in the molecular characterization of genes harboring epigenetic CpG methylation marks and serving as predictive biomarkers for the later onset of non-communicable diseases such as type 2 diabetes and obesity.
Furthermore, posttranslational histone modifications have emerged as central players in the regulation of gene-expression and we aim to functionally characterize specific histone marks, the underlying genes regulated by such modifications, as well as the proteins creating and recognizing these marks. We are using in vitro and ex vivo surrogate disease models, as well as human tissue specimens available from Singapore’s large TCR cohort studies “Growing Up in Singapore Towards a healthy Outcome (GUSTO)” and the “Singapore Adult Metabolism Study (SAMS)” by working closely with our clinician colleagues.In addition, the team utilizes the cynomolgus monkey (Macaca fascicularis) as a suitable non-human primate animal model to derive hypotheses on transgenerational epigenetic pathways aberrantly regulated by nutritional factors leading to intrauterine growth restriction and subsequent metabolic disorders in the offspring.
- Specific Project 1: Molecular characterization of gene-specific CpG methylation pattern via genomic and epigenomic technologies available at SICS and within the collaborative network of the EpiGen consortium (for example gene expression arrays, assessment of CpG DNA methylation marks via pyrosequencing and Sequenom MassArray technologies)
- Specific Project 2: Characterization of epigenetic DNA and histone markers , as well as enzymes in primary myoblasts derived from insulin-resistant and normal subjects (SAMS cohort study).
- Specific Project 3: Studying the functional role of histone modifications and epigenetic enzymes in the cynomolgus monkey (Macaca fascicularis) metabolic disease model and primary cell lines derived from animal tissues.
Wang H, Yu N, Song H, Chen D, Zou Y, Deng W, Lye PL, Chang J, Ng M, Sun ET, Sangthongpitag K, Wang X, Wu X, Khng HH, Fang L, Goh SK, Ong WC, Bonday Z, Stünkel W, Poulsen A, Entzeroth M. (2009) N-Hydroxy-1,2-disubstituted-1H-benzimidazol-5-yl acrylamides as novel histone deacetylase inhibitors: Design, synthesis, SAR studies, and in vivo antitumor activity. Bioorg Med Chem Lett. 2009 Mar 1;19(5):1403-8. Epub 2009 Jan 19
Walter Stünkel , Bee Keow Peh, Yong Cheng Tan, Vasantha M. Nayagam, Xukun Wang, Manuel Salto-Tellez, BinHui Ni, Michael Entzeroth and Jeanette Wood (2007) Functions of the SIRT1 protein deacetylase in cancer. Biotechnol J. 2007 Nov;2(11):1360-8.
Vasantha M. Najagam, Xukun Wang, Yong Cheng Tan, Kee Chuan Goh , Tony Ng, Haishan Wang, Hong Yan Song, BinHui Ni, Michael Entzeroth, and Walter Stünkel. (2006) SIRT1 modulating compounds from high throughput screening as anti-inflammatory and insulin sensitizing agents. J Biomol Screen. , Nov 12
Kee Chuan Goh, Haishan Wang, Niefang Yu, Yifa Zhou, Yin Zheng, ZeYi Lim, Kanda Sangthongpitag, Lijuan Fang, Mark Du, Xukun Wang, A. B. Jefferson, Janet Rose, Blanche Shamoon, Christoph Reinhard, Brad Carte, Michael Entzeroth, BinHui Ni, Marcia L. Taylor, and Walter Stünkel. (2004) PLK1 as a potential drug target in cancer therapy. Drug Dev. Res. Vol. 62 (4), pp. 349-362
Tan, S.-H, Baker, C.C. Stünkel, W. and Bernard, H.-U. (2003) A Transcriptional Initiator Overlaps with a Conserved YY1 Binding Site in the Long Control Region of Human Papillomavirus Type 16. Virology. 305 (2): 486-501
Stünkel, W., Ait-Si-Ali,S., Jones, P.L. and Wolffe, A.P. (2001) Programming the transcriptional state of replicating methylated DNA. J. Biol. Chem. 276 (23): 20743-9
Stünkel, W., Tan, S.-H., Huang, Z., and Bernard, H.-U. (2000) A nuclear matrix attachment region within the E6 oncogene of human papillomavirus-16 silences or activates gene expression depending on the physical state of the DNA. J. Virol. 74:2489-2501.
O'Connor, M.J., Stünkel, W., Koh, C.-H., Zimmermann, H., and Bernard, H.-U. (2000) The differentiation specific factor CDP/hCut represses transcription and replication of human papillomaviruses through a conserved silencing element. J. Virol. 74:401-410
Stünkel, W. and Bernard, H.-U. (1999) The chromatin structure of the Long Control Region of human papillomavirus type 16 represses viral oncoprotein expression. J. Virol. 73:1918-1930
O'Connor, M.J., Stünkel, W., Zimmermann, H., Koh, C.-H., and Bernard, H.-U. (1998) A novel YY1-independent silencer represses the activity of the human papillomavirus type 16 enhancer. J. Virol. 72:10083-10092
Spangenberg, C., Eisfeld, K., Stünkel, W., Luger, K., Flaus, A., Richmond, T.J., Truss, M. and Beato, M. (1998) The mouse mammary tumour virus promoter positioned on a tetramer of histones H3 and H4 binds nuclear factor 1 and OTF1. J. Mol. Biol. 278:725-739.
Stünkel W., Kober, I. and Seifart, K.H. (1997) A nucleosome positioned in the distal promoter region activates transcription of the human U6 gene. Mol. Cell. Biol. 17:4397-4405.
Stünkel W., Kober, I., Kauer, M., Taimor, G. and Seifart, K.H. (1995 ) Human TFIIIA alone is sufficient to prevent nucleosomal repression of a homologous 5S gene. Nucleic. Acids. Res. 23: 109-116.
Ziegler K. and Stünkel, W. (1992) Tissue-selective action of pravastatin due to hepatocellular uptake via a sodium-independent bile acid transporter. Biochim. Biophys. Acta. 1139: 203-209.
Jae Tan Peck Yean
Tan Jun Hao