Praveen Sethupathy, PhD

Assistant Professor

Research Interests

Key words: genomics of gene regulation, microRNAs, epigenomics, computational biology, metabolic disease

Genomic approaches to investigating gene regulatory mechanisms underlying human metabolic disorders

Although every cell in the human body contains the same instruction booklet (genome), different types of cells execute different sets of instructions (genes).  This is what allows a heart cell to behave differently than a neuron, which behaves differently than a skin cell, and so on.  Which genes are activated (or "expressed"), and the extent to which they are activated, is referred to as "gene regulation", and is a key determinant of a cell's function.  Cellular gene regulation is complex, multi-faceted, and dynamic.  The Sethupathy lab is interested in investigating the various strategies that a cell uses to control gene expression, and how these might differ between a normally functioning cell and a disease-predisposed cell.

The majority of the genome does not code for genes; rather, it contains long stretches of “non-coding” regions that harbor interspersed DNA "regulatory elements".  These elements are involved in controlling the degree to which genes are expressed.  Precisely how many regulatory elements there are, and where they reside in the genome, has been largely unknown.  Recent large-scale human genetic studies have revealed that disease-associated common genetic variants (mutations that have spread in the population) are over-represented within non-coding regions (Hindorff*, Sethupathy* et al, 2009, PNAS), providing renewed impetus to expand current catalogs of DNA regulatory elements.

Recent advances in the field of gene regulation have revealed that the way the genome is packaged in the cell could provide some important clues.  Specifically, the packaging material (chromatin) carries different types of "marks", and particular combinations of marks denote different types of regulatory elements.  In previous work, we utilized large-scale experimental and computational genomic methods to profile these marks throughout the genome of human pancreatic islet cells (Stitzel*, Sethupathy*, et al, 2010, Cell Metabolism), which are highly relevant for the development of type 2 diabetes.  We discovered thousands of novel regulatory elements, and provided evidence that several of them are directly affected by common genetic variants that are known to increase risk for type 2 diabetes.  Despite these advances, the current methods for large-scale identification of regulatory elements are not fool-proof.  The Sethupathy lab is interested in developing alternative, complementary strategies to improve genome-wide identification and characterization of regulatory elements (Sethupathy et al, 2011, In revision).

Another important class of regulatory elements is microRNAs.  These are very small RNA molecules, each of which can regulate the expression of hundreds of genes.  In the last decade or so, it has become clear that microRNA mis-function can lead to various human diseases (Sethupathy*, Borel* et al, 2007, American Journal of Human Genetics; Sethupathy and Collins, 2008, Trends in Genetics).  Single-point mutations in or near genomic regions that encode for microRNAs can dramatically alter microRNA expression levels and function, leading to widespread changes in the cellular gene expression profile.  The Sethupathy lab is interested in assessing the role of microRNAs in the etiology of metabolic disorders (Sethupathy*, Vickers*, et al, 2011, In revision), and whether they can be pursued as novel therapeutic targets.

The overall goal of the Sethupathy lab is to characterize gene regulatory networks that may contribute to the molecular pathology of various metabolic diseases, including diabetes and dyslipidemia.  Projects in the lab can involve any of the following: next-generation transcriptomic sequencing, large-scale computational sequence analysis, bioinformatics, genetic association analysis, and molecular assays ranging from quantitative PCR to reporter gene assays.  If you are interested in discussing project ideas further, contact me or come by the office (5091 GMB) any time.

Recent and/or active collaborators:

Francis Collins (NHGRI)
Alan Remaley (NHLBI)
Christy Avery (UNC-CH)
Thomas Tuschl (Rockefeller)
Greg Crawford (Duke)
Alain Laederach (UNC-CH)
Larry Brody (NHGRI)
Massimo Pietropaolo (Michigan)

Publications

Representative original publications:

• P. Sethupathy, M.F. Melgar and F.S. Collins (2011). Bidirectional expression of short transcripts (BEST): promoter lessons instruct discovery of active enhancers. In revision.
• M.L. Stitzel*, P. Sethupathy*, D.S. Pearson, P.S. Chines, L. Song, M.R. Erdos, R. Welch, L.J. Scott, NIH Intramural Sequencing Center Team, M. Boehnke, T. Furey, G.E. Crawford and F.S. Collins (2010). Global epigenomic profiling of human pancreatic islets provides insights into type 2 diabetes susceptibility loci. Cell Metabolism, 12:443-455.
• L.A. Hindorff*, P. Sethupathy*, H.A. Junkins, E.A. Ramos, J.P. Mehta, F.S. Collins and T.A. Manolio (2009). Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. PNAS, 106:9362-9367.
• P. Sethupathy, H. Giang, J.B. Plotkin and S. Hannenhalli (2008). Genome-wide analysis of natural selection on human cis-elements. PLoS One, 10;3(9):e3137.
• P. Sethupathy*, C. Borel*, M. Gagnebin, G.R. Grant, S. Deutsch, T.S. Elton, A.G. Hatzigeorgiou and S.E. Antonarakis (2007). Human miR-155 on chromosome 21 differentially interacts with its polymorphic target in the AGTR1 3’UTR – a mechanism for functional SNPs related to phenotypes. American Journal of Human Genetics, 81:405-413
• Y. Kawahara, B. Zinshteyn, P. Sethupathy, H. Iizasa, A.G. Hatzigeorgiou and K. Nishikura (2007). Redirection of silencing targets by adenosine-to-inosine editing of microRNAs. Science, 2007 Feb. 23:315(5815):1137-40.
• P. Sethupathy, B. Corda and A.G. Hatzigeorgiou (2006). TarBase: A comprehensive database of experimentally supported animal microRNA targets. RNA, 12:192-197.

Representative perspective/review articles:

• P. Sethupathy and F.S. Collins (2008). MicroRNA target site polymorphisms and human disease. Trends in Genetics, 24:489-497.
• P. Sethupathy and S. Hannenhalli (2008). A tutorial of the Poisson Random Field model in population genetics. Advances in Bioinformatics,2008:Article ID 257864.
• P. Sethupathy, M. Megraw and A.G. Hatzigeorgiou (2006).  A guide through current computational approaches for the identification of mammalian microRNA targets. Nature Methods, 3:881-886.

Contact Information

Mailing Address:

CB#7264
Unversity of North Carolina at Chapel Hill
Chapel Hill, NC 27599-7264

Office: 5091 Genetic Medicine Building
Office phone: 919-966-6387
FAX:  919-843-4682

Email: Praveen Sethupathy, PhD