Senior Investigator

Shyam PRABHAKAR, Ph.D.
Group Leader, Computational and Systems Biology
Associate Director, Integrative Genomics
 
Research Focus

Transcriptional Regulation in Development, Evolution and Disease

Transcriptional changes lie at the heart of development, evolution and disease. Organismal development is driven by spatiotemporal changes in gene expression that generate hundreds of cell types from a single totipotent cell. These changes can be rewound by over-expressing a handful of embryonic genes in adult cells. Similarly, morphological differences between species are also thought to be driven largely by transcriptional regulatory changes. Finally, the majority of genetic mutations responsible for common diseases reside within gene-regulatory sequences such as enhancers, promoters and insulators.

We use a combination of wet-lab and dry-lab approaches to study human transcriptional regulation. Regulatory sequences that drove human and primate evolution are a major focus – these are analyzed using comparative genomics, next-generation sequencing (NGS) and in vivo enhancer assays. We are also interested in the more recent regulatory changes that make us different from one another. These are identified by performing histone ChIP-seq on multiple individuals within the target population group. On the disease front, we investigate the transcriptional regulatory mechanisms of autism, lung and colon cancer, and specific immune-related diseases. In this space, we use single-cell RNA-seq and histone ChIP-seq on a large scale.

Methods development:
On the experimental side, we continuously develop and refine NGS-based techniques for whole-genome chromatin profiling and enhancer identification. In parallel, we have created novel computational tools for analyzing NGS data, that draw upon ideas from optimal signal processing, equilibrium thermodynamics and structural biology. We are also developing new statistical methods for associating polymorphisms with chromatin state variation using NGS data. Finally, we have constructed a custom bioinformatic pipeline for single-cell transcriptomic data, with applications in early embryonic development and cancer genomics.



Education

2000 PhD, Applied Physics, Stanford University
1992 BTech, Electronics & Communications Engineering, Indian Institute of Technology, Madras


Professional Appointments

2012-Associate Director, Integrative Genomics, Genome Institute of Singapore
2011-Group Leader, Genome Institute of Singapore
2007-11Senior Research Scientist, Genome Institute of Singapore
2003-07Postdoctoral Fellow, EM Rubin lab, Genomics Division, Lawrence Berkeley National Laboratory
2000-03Postdoctoral Fellow, Samuel Karlin group, Dept. of Mathematics, Stanford University


Honors and Awards


2008 First prize: poster competition at HUGO 13th Human Genome Meeting
2001 American Physical Society Award for Outstanding Doctoral Thesis Research in Beam Physics


Committee and Advisory Board

2013Grant review panel: bilateral grant call issued by BMBF (Germany) and ANR (France)
2014Grant review Panel: A*STAR Young Investigator Grants
2014Organizing committee: 9th Asian Epigenomics Meeting


External Grant

10/2009 - 10/2012(PI) JCOAG03_FG02_2009: Toward a systems biology framework for estrogen signaling integrating technology, biology and computation by Agency for Science, Technology and Research, Joint Council Office, Singapore (SGD 741,000 over 3 years)
09/2013 - 09/2016(PI) JCO1331CFG080: Single Cell Transcriptomic Characterization of Tumour Heterogeneity and Network Analysis of Response to Targeted Therapeutics by Agency for Science, Technology and Research, Joint Council Office, Singapore (SGD 991,000 over 3 years)
08/2011 - 06/2015(co-PI) 1R01MH094714: Epigenetic and Transcriptional Dysregulation in Autism Spectrum Disorder by National Institute of Mental Health, USA (USD 600,000 -direct costs to my group over 4 years)


Selected Publications

  1. Noncoding Origins of Anthropoid Traits and a New Null Model of Transposon Functionalization.
    del Rosario RC, Rayan NA, Prabhakar S.
    Genome Research 2014, accepted.

  2. Dynamic developmental signaling logic underlying lineage bifurcations during human endoderm induction and patterning from pluripotent stem cells.
    Loh KM, Ang LT, Zhang J, Kumar V, Ang J, Auyeong JQ, Lee KL, Nichane M, Poellinger L, Chen Q, Prabhakar S, Weissman IL, Lim B.
    Cell Stem Cell 2014 Jan 8. [Epub ahead of print] Abstract     

  3. Uniform, optimal signal processing of mapped deep-sequencing data.
    Kumar V, Muratani M, Rayan NA, Kraus P, Lufkin T, Ng HH, Prabhakar S.
    Nat Biotechnol 2013 July; 31(7):615-22. Abstract     

  4. TherMos: Estimating protein-DNA binding energies from in vivo binding profiles.
    Sun W, Hu X, Lim MH, Ng CK, Choo S, Castro D, Drechsel D, Guillemot F, Kolatkar PR, Jauch R, Prabhakar S.
    Nucleic Acids Res 2013 Jun 1; 41(11):5555-68 Abstract     

  5. Comprehensive prediction in 78 human cell lines reveals rigidity and compactness of transcription factor dimers.
    Jankowski A, Szczurek E, Jauch R, Tiuryn J, Prabhakar S.
    Genome Res 2013 Aug;23(8):1307-18. Abstract     

  6. In Vivo epigenomic profiling of germ cells reveals germ cell molecular signatures.
    Ng JH, Kumar V, Muratani M, Kraus P, Yeo JC, Yaw LP, Xue K, Lufkin T, Prabhakar S#, Ng HH#. (#: corresponding author)
    Dev Cell 2013 Feb 11; 24(3):324-33. Abstract     

  7. Ncoa3 functions as an essential Esrrb coactivator to sustain embryonic stem cell self-renewal and reprogramming.
    Percharde M, Lavial F, Ng JH, Kumar V, Tomaz RA, Martin N, Yeo JC, Gil J, Prabhakar S, Ng HH, Parker MG, Azuara V.
    Genes Dev 2012 Oct 15; 26(20):2286-98. Abstract     

  8. Integrative model of genomic factors for determining binding site selection by estrogen receptor-alpha.
    Joseph R, Orlov YL, Huss M, Sun W, Kong SL, Ukil L, Pan YF, Li G, Lim M, Thomsen JS, Ruan Y, Clarke ND, Prabhakar S, Cheung E, Liu ET.
    Mol Syst Biol 2010 Dec 21;6:456 Abstract     

  9. Human-specific gain of function in a developmental enhancer.
    Prabhakar S, Visel A, Akiyama JA, Shoukry M, Lewis KD, Holt A, Plajzer-Frick I, Morrison H, FitzPatrick DR, Afzal V, Rubin EM, Noonan JP.
    Science. 2008 Sep;321:1346-50. Abstract     

  10. Accelerated evolution of conserved noncoding sequences in humans.
    Prabhakar S*, Noonan JP*, Pääbo S, Rubin EM (* = equal contribution).
    Science. 2006 Nov;314:786. Abstract     



Complete Publications List



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