Research in our laboratory uses integrative interdisciplinary approaches-merging bioinformatics, functional genomics and molecular biology-to characterize gene regulatory circuitry and epigenomes defining cell states during cellular development, differentiation, and homeostasis. We are particularly interested in mapping gene regulatory networks in embryonic stem cells (ES cells). ES cells can self-renew indefinitely and can differentiate into all derivatives of the three germ layers. These attributes making them an attractive model for regenerative medicine, disease modeling, and drug and toxicity testing. Successful development of ES cell-based therapies not only depends on our understanding of the genes and pathways that constitute the genetic network governing ES cell identity, but also the mechanisms that maintain this intricate homeostatic balance between self-renewal and differentiation.
To define the genetic network controlling the ES cell identity, we have developed a novel computational framework for a systematic meta-analysis of published microarray gene expression data from multiple studies (profiling undifferentiated mouse ES cells and various differentiated cell types) to identify and rank-order genes with characteristic expression patterns in ES cells vs differentiated cells, indicative of their potential roles in regulating ES cells. We have used RNAi-mediated loss-of-function experiments to validate several top-ranked candidates from our computational analysis, and have unearthed tens of genes including with previously unknown roles in ES cell biology. We have successfully characterized the functional roles of some of these genes in ESCs, and their roles in environmentally- and developmentally-responsive pathways. Our ongoing efforts include elucidation of the roles and mechanisms by which these novel regulators of ES cells help maintain the pluripotent state.
Dr. Jothi received his Bachelors degree in 1998 from the University of Madras, and a Ph.D. in 2004 from the University of Texas at Dallas. Subsequently, he completed his postdoctoral training in Systems Biology at NCBI/NLM/NIH and in Epigenetics at NHLBI/NIH before joining NIEHS in 2009 to head the Systems Biology Section. Dr. Jothi received the NIEHS Early Career "Rising Star" Award in 2009. He has published over 35 peer-reviewed articles and book chapters, and serves on the Editorial Boards for PLoS ONE and Frontiers in Bioinformatics and Computational Biology journals.