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Systems Biology Group

Stem Cells, Epigenetics & Gene Regulation

Raja Jothi, Ph.D.
Raja Jothi, Ph.D.
Principal Investigator
Tel 984-287-3696
P.O. Box 12233
Mail Drop A3-03
Durham, N.C. 27709

Research Summary

Raja Jothi, Ph.D., heads the Systems Biology Group within the Epigenetics and Stem Cell Biology Laboratory, and holds a secondary appointment in the NIEHS Biostatistics and Computational Biology Branch.

Understanding how an environmental stimulant affects cellular physiology to give rise to a specific phenotypic outcome is a fundamental step toward understanding development and pathogenesis. During development and in response to environmental insults, various signaling cascades culminate in the activation of key transcription factors and chromatin remodeling enzymes, which collectively establish and/or maintain gene expression programs controlling cell identity.

gene networks
Figure 1. Reconstruction of gene networks controlling cellular response or fate.

The Jothi group is interested in understanding how transcription regulators and epigenetic modifications regulate gene expression programs during cellular development and differentiation. The group uses integrative interdisciplinary approaches — merging systems biology, functional genomics, and biochemistry — to map, reconstruct, and characterize developmentally- and environmentally-responsive gene networks that control fundamental biological processes ranging from transcription and signal transduction to cellular response to changes in the environment.

The group primarily uses embryonic stem (ES) cells as a model system to unravel complex gene networks controlling cell identities. ES cells can self-renew indefinitely and can differentiate into all derivatives of the three germ layers, attributes that make 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 homeostasis, but also the mechanisms that maintain the intricate homeostatic balance between self-renewal and differentiation.

The pluripotent state of ES cells depends upon the coordinated activity of master transcription factors, key signaling pathways, and epigenetic features that include DNA methylation and histone modifications. Although many key determinants of ES cell identity have been identified, it is not fully clear how ES cells maintain a stable program of self-renewal while also allowing alternate gene expression programs to induce differentiation. Mechanisms that coordinate the activities of master regulators, signaling pathways, and epigenetic features remain poorly understood, owing largely to incomplete characterization of the genetic network underlying ES cells.

To better understand the genetic network governing ES cell self-renewal and differentiation, the group uses interdisciplinary approaches to generate testable hypotheses. The group's research program is made up of two components: computational and laboratory. Research within the group, for the most part, is data-driven, through computational analyses of published and in-house-generated heterogeneous high-throughput genomic/proteomic datasets with the goal of generating testable hypotheses. The laboratory component of the research program provides the means to not only test some of the hypotheses that come out of computational analyses, but also to perform biochemical experiments to gain mechanistic insights. Over the years, the group has successfully identified and characterized many genes with previously unknown roles in ES cell biology.

Major areas of research:

  • Chromatin, epigenetics and gene regulatory networks
  • Embryonic stem cell self-renewal and pluripotency
  • Methods development for high-throughput data analyses

Current projects:

  • Reconstruction and characterization of gene networks regulating stem cell identity
  • Investigation into how signaling cascades instruct epigenetic or transcriptional programs controlling cell fate
  • Elucidation of mechanisms regulating transcription during productive elongation

Jothi earned his Bachelor’s degree in 1998 from the University of Madras and a Ph.D. in 2004 from the University of Texas at Dallas. He received his postdoctoral training in Computational Biology and Epigenetics from the National Institutes of Health laboratories of Teresa Przytycka (NCBI/NLM) and Keji Zhao (NHLBI) before joining NIEHS in 2009. He has published more than 50 peer-reviewed articles and book chapters, and serves on the Editorial Boards for PLoS ONE and Frontiers in Bioinformatics and Computational Biology journals.

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