Directory

Systems genomics approaches to identify and validate biological mechanisms underlying cardio-metabolic disease. The association of DNA sequence variation (single nucleotide polymorphisms or SNPs) and gene expression with phenotypic traits represent the core of genome biology. However, the inadequacy of traditional SNP-centric analysis, or individual gene expression profiles for revealing biological mechanisms underlying susceptibility to common disorders necessitates alternative analytic approaches. We apply integrated, ensemble-based bioinformatic strategies (systems genomics) to interrogate the cumulative effects of genetic polymorphisms and gene-set expression patterns in biological mechanisms. These approaches lead to the identification of novel causal mechanisms underlying a variety of cardio-metabolic traits including obesity, type 2 diabetes and coronary artery disease. We follow-up on novel disease-related gene candidates by functional genomics analysis in cell-based and animal model systems.

Nutrigenomics studies to elucidate metabolic responses to nutrient variation. The response of the transcriptome to nutritional cues (e.g. excess or deficiency of nutrients, caloric restriction) allows one to infer metabolic adaptations to altered energy supply. We are broadly interested in understanding the effects of caloric restriction and dietary nutrient restriction in key metabolic tissues in humans and animal models. These studies generate important insights into tissue-specific transcriptomic responses to nutrients in the context of longevity and metabolic health.

Collaborations involving other disease areas. In addition to the above-mentioned research areas related to cardio-metabolic disease and nutrigenomics, we collaborate extensively with national and international investigators for bioinformatic analysis of first-generation ‘omics’ and next-generation sequencing data on diverse research projects in cancer, infectious disease, neurobiology and exercise physiology.

1. Wilkins, J., Ghosh, P., Vivar, J., Chakraborty, B., and Ghosh, S. Exploring the associations between systemic inflammation, obesity and healthy days: a health related quality of life (HRQOL) analysis of NHANES 2005-2008. BMC Obesity, 5:21(2018)

2. Gurley, S., Ghosh, S., Stacy, J., Azushima, K., Sakban, R., George, S., Maeda, M., Meyer, T., and Coffman, T. Inflammation and immunity pathways regulate genetic susceptibility to diabetic nephropathy. Diabetes, 67, 2096-2106 (2018) 

3. Chan, J.P., Wong, B.H., Chin, C.F., Galam, D.L.A., Foo, J.C., Wong, L.C., Ghosh, S., Wenk, M.R., Cazenave-Gassiot, A., and Silver, D. The lysolipid transporter Mfsd2a regulates lipogenesis in the developing brain. PLoS Biology, https://doi.org/10.1371/journal.pbio.2006443

4. Singh, B.K., Sinha, R.A., Tripathy, M., Mendoza, A., Ohba, K., Sy, J.A.C., Xie, S.Y., Zhou, J., Ho, J.P., Chang, C., Wu, Y., Giguere, V., Bay, B.H., Vanacker, J.M., Ghosh, S., Gauthier, K., Hollenberg, A.N., McDonnell, D.P., and Yen, P. Thyroid hormone receptor and ERRa coordinately regulate mitochondrial fission, mitophagy, biogenesis and function. Science Signaling, 11, 536, 5855 (2018)

5. Chang, J.S., Ghosh, S., Newman, S., and Salbaum, J.M. A map of the PGC-1a and NT-PGC-1a regulated transcriptional network in brown adipose tissue. Scientific Reports, 8, 7876 (2018)

6. Yan, T., Ooi, W.F., Qamra, A., Cheung, A., Ma, D., Sundaram, G.M., Xu, C., Xing, M., Poon, L., Wang, J., Loh, Y.P., Ho, J.H.J., Ng, J.J.Q., Ramlee, M.K., Aswad, L., Rozen, S.G., Ghosh, S., Bard, F., Sampath, P., Tergaonkar, V., Davies, J.O.J., Hughes, J.R., Goh, E., Bi, X., Fullwood, M.J., Tan, P., and Li. S. HoxC5 and miR-615-3p target newly evolving genomic regions to repress hTERT and inhibit tumorigenesis. Nature Communications, 9, 100 (2018)

7. Kitagawa, M., Liao, P.J., Lee, K.H., Wong, J., See, C.S., Minami, N., Sampetrean, O., Saya, H., Dai, L., Prabhu, N., Go, K.D., Sobota, R., Larsson, A., Nordlund, P., McCormick, F., Ghosh, S., Epstein, D., Dymock, B., and Lee, S.H. Dual blockade of the lipid kinase PIP4Ks and mitotic pathways leads to cancer-selective lethality. Nature Communications doi:10.1038/s41467-017-02287-5 (2017)

8. Gan, E.S., Cheong, W.F., Chan, K.R., Ong, E.Z., Chai, X., Tan, H.C., Ghosh, S., Wenk, M.R., and Ooi, E.E. Hypoxia enhances antibody-dependent dengue virus infection. EMBO J., 36,1348-1363, e201695642 DOI 10.15252/embj.201695642 (2017)

9. Ghosh, S., and Bouchard, C. Convergence between biological, behavioural and genetic determinants of obesity. Nature Reviews Genetics, 18, 731-748, doi:10.1038/nrg.2017.72 (2017)

10. Bai, Z., Chai, X., Yoon, M.J., Kim, H.J., Lo, K.A., Zhang, Z., Xu, D., Siang, D.T.C., Walet, A.C.E., Xu, S., Chia, S.Y., Chen, P., Yang, H., Ghosh, S., and Sun, L. Dynamic transcriptome changes during adipose tissue energy expenditure reveal critical roles for long noncoding RNA regulators. PLOS Biology, 15(8):e2002176, doi: 10.1371/journal.pbio.2002176 (2017)

11. Ghosh, S., Forney, L.A., Wanders, D., Stone, K.P., and Gettys, T.W. An integrative analysis of tissue-specific transcriptomic and metabolomics responses to short-term dietary methionine restriction in mice. PLOS ONE, https://doi.org/10.1371/journal.pone.0177513 (2017)

12. Ler, L.D., Ghosh, S., Chai, X., Thike, A.A., et al. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Science Translational Medicine, 9, doi:10.1126/scitranslmed.aai8312 (2017)

13. Liu, J.J., Ghosh, S., Kovalik, J.P., Ching, J., Choi, H.W., Tavintharan, S., Ong, C.N., Sum, C.F., Summers, S.A., Tai, E.S., and Lim, S.C. Profiling of plasma metabolites suggests altered mitochondrial fuel usage and remodeling of sphingolipid metabolism in individuals with type 2 diabetes and kidney disease. Kidney International Reports, 2, 470-480, http://dx.doi.org/10.1016/j.ekir.2016.12.003 (2017)

14. Chan, K.R., Wang, X., Saron, W.A.A., Gan, E.S., Tan, H.C., Mok, D.Z.L., Zhang, S.L., Lee, Y.H., Liang, C., Wijaya, L., Ghosh, S., Cheung, Y.B., Tannenbaum, S.R., Abraham, S.N., St John, A.L., How, J.G.H., and Ooi, E.E. Cross-reactive antibodies enhance live attenuated virus infection for increased immunogenicity. Nature Microbiology, doi:10.1038/nmicrobiol.2016.164 (2016)

15. Ghosh, S., Kruger, C., Wicks, S., Simon, J., Kumar, G., Johnson, W.D., Mynatt, R.L., Noland, R.C., and Richards, B.K. Short chain acyl-CoA dehydrogenase deficiency and short-term high-fat diet perturb mitochondrial energy metabolism and transcriptional control of lipid-handling in liver. Nutrition and Metabolism, 13:17, doi:10.1186/s12986-016-0075-0 (2016)

16. Vandanmagsar, B., Warfel, J.D., Wicks, S.E., Ghosh, S., Salbaum, J.M., Burk, D., Dubuisson, O.S., Mendoza, T.M., Zhang, J., Noland, R.C., and Mynatt, R.L. Impaired Mitochondrial Fat Oxidation Induces FGF21 in Muscle. Cell Reports, pii: S2211-1247(16)30501-0. doi: 10.1016/j.celrep.2016.04.057 (2016)

17. Cialdella-Kam, L., Nieman, D.C., Knab, A.M., Shanely, R.A., Meaney, M.P., Jin, F., Sha, W. and Ghosh, S. A Mixed Flavonoid-Fish Oil Supplement Induces Immune-Enhancing and Anti-inflammatory Transcriptomic Changes in Adult Obese and Overweight Women – A Randomized Controlled Trial. Nutrients, 8, 277 doi:10.3390/nu8050277 (2016)

18. Lam, Y.Y., Ghosh, S., Civitarese, A.E., and Ravussin, E. Six-month calorie restriction in overweight individuals elicits transcriptomic response in subcutaneous adipose tissue that is distinct from effects of energy deficit. Journal of Gerontology:Biological Sciences pii: glv194 (2015)

19. Ghosh, S., Vivar, J., Nelson, C.P., Willenborg, C., Segre, A.V., Makinen, V.P., Nikpay, M., Erdmann, J., Blankenberg, S., O’Donnell, C., Marz, W., Laaksonen, R., Stewart, A.F., Epstein, S.E., Shah, S.H., Granger, C.B., Hazen, S.L., Kathiseran, S., Reilly, M.P., Yang, X., Quertermous, T., Samani, N.J., Schunkert, H., Assimes, T.L., and McPherson, R. Systems genetics analysis of genome-wide association study reveals novel associations between key biological processes and coronary artery disease. Arteriosclerosis Thrombosis and Vascular Biology,35,1712-1722 (2015)

20. Rankinen, T., Sarzynski, M.A., Ghosh, S. and Bouchard, C. Are there genetic paths common to obesity, cardiovascular disease outcomes and cardiovascular risk factors? Circulation Research, 116, 909-922 (2015); doi:10.1161/CIRCRESAHA.116.302888