During development, 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.

The Jothi Lab 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 and molecular biology, and functional genomics—to map, reconstruct, and characterize 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 cells (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 interdiscplinary 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.


Research Fellow
Senthilkumar Cinghu
Senthilkumar Cinghu, Ph.D.

Senthil is interested in identifying key determinants of emrbyonic stem cell identity. He obtained his Ph.D. from the University of Madras. Before joining the lab, he was postdoctoral fellow in Gary Stein lab at UMass Medical School.

Amanda Conway
Amanda Conway, Ph.D.

Amanda's uses embryonic stem cell as a model system to investigate nuclear export protein CRM1's role in developmental gene regulation. She received her Ph.D. from Duke University for her work on CRM1 in CALM-AF10 Leukemias.

Justin Kosak
Justin Kosak, M.S.

Justin provides scientific and technical support to trainees in the Jothi Lab. He oversees lab operation and animal studies. He received his Bachelors degree from the NC State University and and his Masters degree from the University of Pennsylvania.

Senior Investigator
Raja Jothi
Raja Jothi, Ph.D.

Raja is interested in understanding how transcription regulators and epigenetic modifications regulate gene expression programs during development and cellular differentiation. He received his Ph.D. in computer science from the University of Texas at Dallas.

Postdoctoral Fellow
Andrew Oldfield
Andrew Oldfield, Ph.D.

Andrew's research focusses on NF-Y's role in the regulation of chromatin accessibility at enhancers and promoters. He received his Ph.D. from Universite Paris VI Pierre & Marie Curie. Before joining the group, he was a post-doctoral fellow at University College London.

Research Fellow
Rajneesh Pathania
Rajneesh Pathania, Ph.D.

Rajneesh uses mouse mammary tumor model to understand cancer stem cell (CSC) heterogeneity and their metastasis potential in triple negative breast cancer. He received his Ph.D. from Georgia Regents University for his his work on Dnmt1 in CSCs and tumors.

Research Fellow
Pengyi Yang
Pengyi Yang, Ph.D.

Pengyi, a computational biologist, is intersted in understanding how signaling cascades instruct epigenetic and/or transcriptional networks regulating cell fate decisions. He received his Ph.D. in Bioinformatics from the University of Sydney.



  • Zheng X, Yang P, Lackford B, Bennett BD, Wang L, Li H, Wang Y, Miao Y, Foley JF, Fargo DC, Jin Y, Williams CJ, Jothi R, Hu G. CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State. Stem Cell Reports 7(5):897-910, 2016. [Pubmed]
  • Minard AY, Tan SX, Yang P, Fazakerley DJ, Domanova W, Parker BL, Humphrey SJ, Jothi R, Stöckli J, James DE. mTORC1 Is a Major Regulatory Node in the FGF21 Signaling Network in Adipocytes. Cell Reports 17(1):29-36, 2016. [Pubmed]
  • Yang P, Patrick E, Humphrey SJ, Ghazanfar S, James DE, Jothi R, Yang JY. KinasePA: Phosphoproteomics data annotation using hypothesis driven kinase perturbation analysis. Proteomics 16(13):1868-71, 2016. [Pubmed]
  • Yang P, Humphrey SJ, James DE, Yang YH, Jothi R*. Positive-unlabeled ensemble learning for kinase substrate prediction from dynamic phosphoproteomics data. Bioinformatics 32(2):252-9, 2016. [Pubmed]


  • Hoffman NJ, Parker BL, Chaudhuri R, Fisher-Wellman KH, Kleinert M, Humphrey SJ, Yang P, Holliday M, Trefely S, Fazakerley DJ, Stockli J, Burchfield J, Jensen T, Jothi R, Kiens B, Wojtaszewski JFP, Richter EA, James DE. Global phosphoproteomic analysis of human skeletal muscle reveals a network of exercise regulated kinases and AMPK substrates. Cell Metabolism 22(5):922-35, 2015. [Pubmed]
  • Yang P, Zheng X, Jayaswal V, Hu G, Yang JY, Jothi R*. Knowledge-based analysis for detecting key signaling events from time-series phosphoproteomics data. PLoS Computational Biology 11(8):e1004403, 2015. [Pubmed]
  • Pathania R, Ramachandran S, Elangovan S, Padia R, Yang P, Cinghu S, Veeranan-Karmegam R, Arjunan P, Gnana-Prakasam JP, Sadanand F, Pei L, Chang CS, Choi JH, Shi H, Manicassamy S, Prasad PD, Sharma S, Ganapathy V, Jothi R, Thangaraju M. DNMT1 is essential for mammary and cancer stem cell maintenance and tumorigenesis. Nature Communications 6:6910, 2015. [Pubmed]


  • Oldfield AJ1, Yang P1, 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, Molecular Cell 55(5):708-22, 2014 (1Co-first authors) [Pubmed]
  • Cinghu S1, Yellaboina S1, 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. 111(16):E1581-90, 2014. (1Co-first authors) [Pubmed]
  • Takeda Y, Kang HS, Freudenberg J, DeGraff LM, Jothi R, Jetten AM. Retinoic acid-related orphan receptor γ (RORγ): A Novel Participant in the Diurnal Regulation of Hepatic Gluconeogenesis and Insulin Sensitivity, PLoS Genetics 10(5):e1004331, 2014. [Pubmed]
  • Wang L, Du Y, Ward JM, Shimbo T, Lackford L, Zheng, X, Miao Y-l, Zhou B, Han L, Fargo DC, Jothi R, Williams CJ, Wade PA, Hu G. INO80 Facilitates Pluripotency Gene Activation in Embryonic Stem Cell Self-Renewal, Reprogramming, and Blastocyst Development, Cell Stem Cell 14(5):575-91, 2014. [Pubmed]
  • Lackford B, Yao C, Charles GM, Weng L, Zheng X, Choi EA, Xie X, Wan J, Xing Y, Freudenberg JM, Yang P, Jothi R, Hu G, Shi Y. Fip1 regulates mRNA alternative polyadenylation to promote stem cell self-renewal, EMBO J. 33(8):878-89, 2014. [Pubmed]
  • Li R, Mav D, Grimm SA, Jothi R, Shah R, Wade PA. Fine-tuning of epigenetic regulation with respect to promoter CpG content in a cell type-specific manner, Epigenetics 9(5):747-59, 2014. [Pubmed]


  • Li L1, Freudenberg J1, Cui K, Dale R, Song SH, Dean A, Zhao K, Jothi R*, Love PE*. Ldb1-nucleated transcription complexes function as primary mediators of global erythroid gene activation. Blood, 121(22):4575-85, 2013. (*Co-corresponding authors; 1Co-first authors) [Pubmed] [PDF] [Text]
  • Menendez D1, Nguyen TA1, Freudenberg JM1, Mathew VJ, Anderson CW, Jothi R*, Resnick MA*. Diverse stresses dramatically alter genome-wide p53 binding and transactivation landscape in human cancer cells. Nucleic Acids Research 41(15):7286-301, 2013 (*Co-corresponding authors; 1Co-first authors) [Pubmed] [PDF] [Text]


  • Freudenberg JM1, Ghosh S1, Lackford BL1, 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 Research 40(8):3364-77, 2012. (*Co-corresponding authors; 1Co-first authors [Pubmed] [PDF] [Text]
  • Zheng X, Dumitru R, Lackford B, Freudenberg JM, Singh AP, Archer TK, Jothi R, Guang Hu. Cnot1, Cnot2, and Cnot3 maintain mouse and human ES cell identity and inhibit extraembryonic differentiation. Stem Cells 30(5):910-22, 2012. [Pubmed]
  • Chalancon G, Ravarani R, Santhanam B, Martinez-Arias A, Aravind L, Jothi R, Babu MM. Interplay between gene expression noise and regulatory network architecture. Trends in Genetics 28:221-32, 2012. [Pubmed]
  • Agarwal SK*, Jothi R*. Genome-wide characterization of menin-dependent H3K4me3 reveals a specific role for menin in the regulation of genes implicated in MEN1-like tumors
    PLoS ONE 7(5):e37952, 2012.
  • Narlikar L, Jothi R*. ChIP-Seq data analysis: identification of protein-DNA binding sites with SISSRs peak-finder. Methods in Molecular Biology 802:305-22, 2012. [Pubmed] [PDF]


  • Ho L, Miller EL, Ronan JL, Ho W, Jothi R*, Crabtree GR*. esBAF facilitates pluripotency by conditioning the genome for LIF/STAT3 signaling and by regulating Polycomb function. Nature Cell Biology 13(8):903-913, 2011. (*Co-corresponding authors) [Pubmed] [PDF] [Text]
  • Wei G1, Abraham BJ1, Yagi R1, Jothi R1, Cui K, Sharma S, Narlikar L, Northrup D, Tang Q, Paul WE, Zhu J, Zhao . Genome-wide analyses of GATA3-mediated gene regulation in distinct T cell types. <Immunity 35(2):299-311, 2011. (1Co-first authors) [Pubmed] [PDF] [Text]
  • Li L, Jothi R, Cui K, Lee JY, Cohen T, Gorivodsky M, Tzchori I, Zhao Y, Hayes SM, Bresnick EH, Zhao K, Westphal G, Love PE. Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells. Nature Immunology 12(2):129-136, 2011.
  • Yellaboina S, Tasneem A, Zaykin DV, Raghavachari B, Jothi R*. DOMINE: a comprehensive collection of known and predicted domain-domain interactions. Nucleic Acids Research, 39(Database issue):D730-735, 2011. [Database Website]
  • Yu S1, Cui K1, Jothi R1, Zhao DM, Jing X, Zhao K, Xue. GABP controls a critical transcription regulatory module that is essential for maintenance and differentiation of hematopoietic stem/progenitor cells. Blood 117(7):2166-78, 2011. (1Co-first authors).


  • Yu S, Zhao DM, Jothi R, Xue HH. Critical requirement of GABPα for normal T cell development. Journal of Biological Chemistry 285(14):10179-10188, 2010 [Pubmed] [PDF] [Text]


  • Liu M, Chen XW, Jothi R. Knowledge-Guided Inference of Domain-Domain Interactions from Incomplete Protein-Protein Interaction Networks. Bioinformatics 25: 2492-2499, 2009. [Pubmed] [PDF] [Text]
  • Jothi R1,*, Balaji S1, Wuster S, Grochow JA, Gsponer J, Przytycka TM, Aravind L, Babu MM*. Genomic analysis reveals a tight link between transcription factor dynamics and regulatory network architecture. Molecular Systems Biology, 5:294, 2009. (1Co-first authors) [Pubmed] [PDF] [Text]
  • Barski A1, Jothi R1, Cuddapah S1, Cui K, Roh TY, Schones DE, Zhao K. Chromatin poises miRNA and protein-coding genes for expression. Genome Research 19(10):1742-1751, 2009. (1Co-first authors) [Pubmed] [PDF] [Text] [Cover page]
  • Kallin E, Cao R, Jothi R, Xia K, Cui K, Zhao K, Zhang Y. Genome wide uH2A localization analysis highlights Bmi1-dependent deposition of the mark at repressed genes. PLoS Genetics Jun;5(6):e1000506, 2009. (1Co-first authors) [Pubmed] [PDF] [Text]
  • Ho L1, Jothi R1, Ronan JL, Cui K, Zhao K, Crabtree GR. An embryonic stem cell chromatin remodeling complex, esBAF, is an essential component of the core pluripotency transcriptional network. Proc. Natl. Acad. Sci. 106(13):5187-5191, 2009. (1Co-first authors) [Pubmed] [PDF] [Text]
  • Cuddapah S1, Jothi R1, Schones DE, Barski A, Roh TY, Cui K, Zhao K. Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Research 19(1):24-32, 2009. (1Co-first authors) [Pubmed] [Text] [PDF] [F1000]
  • Jothi R, Cuddapah C, Barski A, Cui K, Zhao K. Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Research 36(16):5221-31, 2008. [Pubmed] [PDF] [Text] [Download SISSRs]
  • Jothi R*, Raghavachari B. Improved approximation algorithms for the single-sink buy-at-bulk network design problem. Journal of Discrete Algorithms 7(2):249-255, 2009.(extended abstract appeared in Proc. 9th Scandinavian Workshop on Algorithm Theory, LNCS 3111, 336-348, 2004).
  • Jothi R*, Raghavachari B. Degree-bounded minimum spanning trees. Discrete Applied Mathematics 157(5):960-970, 2009. (extended abstract appeared in Proc.16th Canadian Conference on Computational Geometry, 192-195, 2004).


  • Jothi R, Cuddapah S, Barski A, Cui K, Zhao K. Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Research 36(16):5221-31, 2008. [PDF] [Text] [Download SISSRs]
  • Raghavachari B, Tasneem A, Przytycka TM, Jothi R*. DOMINE: A database of protein domain interactions. Nucleic Acids Research 36(Database issue):D656-61, 2008. [PDF] [Text] [Database Website]
  • Przytycka TM, Jothi R, Aravind L, Lipman DJ. Differences in evolutionary pressure acting within highly conserved ortholog groups. BMC Evolutionary Biology 8:208, 2008. [PDF] [Text]
  • Jothi R, Przytycka TM. Computational approaches to predict protein-protein and domain-domain interactions. Bioinformatics Algorithms: Techniques and Applications, (Eds: Mondoiu I and Zelikovsky I), Wiley Press, 2008.[PDF]


  • Jothi R*, Przytycka TM*, Aravind L. Discovering functional linkages and uncharacterized cellular pathways using phylogenetic profile comparisons: A comprehensive assessment. BMC Bioinformatics 8:173, 2007. (*Co-corresponding authors) [PDF] [Text]
  • Kann MG,Jothi R, Cherukuri PF, Przytycka TM. Predicting protein domain interactions from co-evolution of conserved regions. Proteins 67(4):811-20, 2007.
  • Jothi R*, Raghavachari B. Approximating the k-Traveling Repairman Problem with Repairtimes. Journal of Discrete Algorithms 5(2), 293-303, 2007 (extended abstract appeared in Proc. Latin American Theoretical INformatics, LNCS 2976, 423-433, 2004).


  • Guimares K, Jothi, Zotenko E, Przytycka TM*. Predicting Domain-Domain Interactions Using a Parsimony Approach. Genome Biology 7(11): R104, 2006. [PDF] [Text]
  • Jothi R*, Cherukuri PF, Tasneem A, Przytycka TM*. Co-evolutionary analysis of domains in interacting proteins reveals insights into domain-domain interactions mediating protein-protein interactions. Journal of Molecular Biology 362(4):861-875, 2006. (*Co-corresponding authors) [PDF] [Text] [Supplementary Material] [F1000]
  • Decomposition of overlapping protein complexes: A graph theoretical method for analyzing static and dynamic protein associations. Zotenko E, Guimares K, Jothi R, and Przytycka TM*. Algorithms for Molecular Biology, 1:2, April 2006 [PDF] [Text]
  • Jothi R*, Zotenko E, Tasneem T, and Przytycka TM*. COCO-CL: Hierarchical clustering of homology relations based on evolutionary correlations. Bioinformatics 22(7), 779-788, 2006. [PDF] [Text] [Supplementary Material]
  • Gong C, Sarac K, Daescu O, Raghavachari B, Jothi R. Load Balanced Agent Activation for Value Added Network Services, Computer Communications 29(11):1905-1916, 2006.


  • Jothi R, Kann MG, Przytycka TM. Predicting protein-protein interaction by searching evolutionary tree automorphism space. Bioinformatics 21 (Suppl 1): i241-i250, 2005. [PDF] [Website] (presented at the 13th Annual International Conference on Intelligent Systems for Molecular Biology (ISMB) 2005).
  • Jothi R*, Raghavachari R. Approximation algorithms for the capacitated minimum spanning tree problem and its variants in network design. ACM Transactions on Algorithms 1(2):265-282, 2005. (an extended abstract appeared in Proc. 31st International Colloquium on Automata, Languages and Programming (ICALP), LNCS 3142, 805-818, 2004).
  • Wang J, Vokkarane V, Jothi R, Qi X, Raghavachari B, Jue J. Dual-homing protection in IP-over-WDM networks. IEEE/OSA Journal of Lightwave Technology 23(10):3111-3124, 2005. [PDF] (an extended abstract appeared in Proc. IEEE International Conference on Communications (ICC), Vol. 3, 1644-1648, 2004).


  • Jothi R*, Raghavachari B.Survivable network design: The capacitated minimum spanning network problem. Information Processing Letters 91(4): 183-190, 2004.
  • Daescu O, Jothi R, Raghavachari B, Sarac K. Optimal placement of NAK suppressing agents for reliable multicast: A partial deployment case.
    in Proc. 19th ACM Symposium on Applied Computing (SAC), pp. 334-338, 2004
  • Jothi R* . A note on Altinkemer-Gavish's algorithm for the design of tree networks. Proc. 7th INFORMS Telecommunications Conference, pp. 78-80, 2004.
  • Jothi R*, Raghavachari B. Revisiting Esau-Williams' algorithm: On the design of local access networks. Proc. 7th INFORMS Telecommunications Conference 104-107, 2004.
  • strong>Jothi R*, Vokkarane V. Threshold-based differentiated intermediate-node initiated (TDINI) signaling for optical burst-switched networks. <Proc. 7th INFORMS Telecommunications Conference, 2004.
  • Jothi R*, Raghavachari B*. Dynamic capacitated minimum spanning trees. Proc. 3rd IEEE International Conference on Networking (ICN),ISBN 0-86341-326-9, 2004.
  • Placement of proxy servers to spport server-based reliable multicast. Jothi R*, Raghavachari B*. Proc. 3rd IEEE International Conference on Networking (ICN),ISBN 0-86341-326-9, 2004.
  • Jothi R*, Raghavachari B*. Design of local access networks. Proc. 15th IASTED Intl. Conf. on Parallel and Distributed Computing and Systems (PDCS), 883-888, 2003.


  • Jothi R*, Raghavachari B*, Varadarajan S*. A 5/4-approximation algorithm for minimum 2-edge-connectivity (Theorem 6.1 is withdrawn) Proc. 14th ACM-SIAM Symposium on Discrete Algorithms (SODA), ACM Press, 725-734, 2003.


    Postdoctoral Fellowships are immediately available in the Jothi Lab at the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH) to study mechanisms of gene regulation in embryonic and cancer stem cells. Dr. Jothi's group is interested in understanding how transcription regulators and chromatin modifications regulate gene expression programs during cellular development and differentiation. Successful candidates will undertake exciting new projects in the general areas of Epigenetics and Stem Cell Biology (or) Computational Biology.

    Qualifications: Candidates should have obtained a Ph.D. or M.D. degree in Biological or Computational Sciences within the last 5 years. For laboratory positions, the candidate should have a strong background in molecular biology and/or protein biochemistry; experience in stem cell biology, development, chromatin immunoprecipitation (ChIP) or RNAi is highly desirable. For Bioinformatics positions, the applicant should possess extensive programming skills; candidates with experience in the application of computational methods to high-throughput genomic and/or proteomic data are highly desirable. Excellent communications skills and ability to work with a highly interactive interdisciplinary team of researchers are essential.

    Location: NIEHS main campus in the Research Triangle Park (RTP), North Carolina. The RTP is the largest research park in US, located in the Raleigh, Durham, Cary, and Chapel Hill metropolitan area and is within driving distance to Duke University, University of North Carolina-Chapel Hill, and North Carolina State University.

    Pay & Benefits: Successful candidates will be offered competitive stipend/salary commensurate with number of years of postdoctoral experience and accomplishments.

    To Apply: Please send CV and the names of three references via email to Dr. Raja Jothi


  • This is a personal website, maintained by Dr. Raja Jothi; The content (text, images, views, and opinions) expressed on this website do not state or reflect those of the U.S. Government, Department of Health and Human Services (DHHS), National Institutes of Health (NIH), or National Institute of Environmental Health Sciences (NIEHS). Click here for the official Government website of the Jothi Lab.