Raja Jothi, Ph.D.
Epigenetics & Stem Cell Biology Laboratory / Systems Biology Group
Building 101, Room A314
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
Research in our laboratory uses integrative interdisciplinary approaches (merging bioinformatics, functional genomics and molecular biology) to characterize gene regulatory networks and epigenomes that underline cell states during development, differentiation, and homeostasis. We are particularly interested in embryonic stem cells (ES cells), which are ideal model systems for unraveling complex gene networks controlling cell identities. 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 the intricate homeostatic balance between self-renewal and differentiation.
Toward reconstruction of the genetic network controlling the ES cell identity, we have developed a computational framework that leverages relative gene expression across various cell types/states from independent perturbation experiments (genetic, exposure, differentiation, etc) to rank-order genes based on how likely they are to have a role in the maintenance of the ES cell identity. Using RNAi-mediated loss-of-function experiments, we have identified dozens of genes with previously unknown roles in ES cell biology. We have successfully characterized the mechanistic roles of some of the genes we have identified to have roles in ESC maintenance. Our ongoing efforts include elucidation of the roles and mechanisms by which other candidates 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 40 peer-reviewed articles and book chapters, and serves on the Editorial Boards for PLoS ONE and Frontiers in Bioinformatics and Computational Biology journals.
Oldfield AJ, Yang P, Conway AE, Cinghu S, Freudenberg JM, Yellaboina S, Jothi R. Histone-Fold Domain Protein NF-Y Promotes Chromatin Accessibility for Cell Type-Specific Master Transcription Factors. Mol Cell. 2014;55(5):708-22.
Cinghu S, Yellaboina S, Freudenberg JM, Ghosh S, Zheng X, Oldfield AJ, Lackford BL, Zaykin DV, Hu G, Jothi R. Integrative framework for identification of key cell identity genes uncovers determinants of ES cell identity and homeostasis. Proc Natl Acad Sci U S A. 2014;111(16):E1581-90.
Freudenberg JM, Ghosh S, Lackford BL, Yellaboina S, Zheng X, Li R, Cuddapah S, Wade PA, Hu G, Jothi R. Acute depletion of Tet1-dependent 5-hydroxymethylcytosine levels impairs LIF/Stat3 signaling and results in loss of embryonic stem cell identity. Nucleic Acids Res. 2012;40(8):3364-77.
Ho L, Miller EL, Ronan JL, Ho WQ, Jothi R, Crabtree GR. esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signalling and by regulating polycomb function. Nat Cell Biol. 2011;13(8):903-13.
Jothi R, Balaji S, Wuster A, Grochow JA, Gsponer J, Przytycka TM, Aravind L, Babu MM. Genomic analysis reveals a tight link between transcription factor dynamics and regulatory network architecture. Mol Syst Biol. 2009;5:294.