Bio

Honors & Awards


  • Graduate Student Fellowship Award, University of Nebraska Medical Center (2008)
  • First place, Oral presentation, Midwest Student Biomedical Research Forum (2009)
  • Harris Award for Graduate Students in Cancer Research, University of Nebraska Medical Center (2010)

Professional Education


  • Doctor of Philosophy, University of Nebraska Medical Center (2010)
  • Master of Science, University Of Mumbai (2005)
  • Bachelor of Science, Ramanarain Ruia College (2003)

Stanford Advisors


Research & Scholarship

Current Research and Scholarly Interests


The discovery that insulin-producing β-cells can be generated from cell sources within and outside the pancreas is of fundamental importance in terms of developing novel treatment strategies for diabetes. A major caveat to this is our relatively poor understanding of the players involved in this process and the lack of molecular characterization of the ‘converted’ β-cells. This knowledge is key to our success in enhancing this process to its maximum therapeutic potential and efficiency. In this context, recent work has shown that α-cells can be used as a source to generate β-cells under conditions of near-total β-cell depletion in mice. However the molecular mechanisms regulating α-cell identity are unknown. This knowledge would allow us to harness the potential of α-cells to give rise to β-cells in diabetic patients where pancreatic α-cells tend to be in abundant supply within the pancreas. My work in the laboratory has elucidated the role of two genes in maintaining α-cell identity: Dnmt1 and Arx. Dnmt1, a DNA methyltransferase methylates DNA and is involved in gene repression. Arx is a transcription factor that is essential for α-cell specification during embryogenesis. My work demonstrates that conditional in vivo inactivation of Dnmt1 and Arx in adult α-cells causes them to convert into insulin producing β-like-cells demonstrating the necessity of these two factors in maintaining α-cell fate. Further functional characterization of these ‘converted’ cells will elucidate the extent to which α-to- β-cell conversion has occurred in these animals. I am also assessing the individual contributions of Dnmt1 and Arx in maintaining adult α-cell identity.

Publications

Journal Articles


  • The Transcription Factor Encyclopedia GENOME BIOLOGY Yusuf, D., Butland, S. L., Swanson, M. I., Bolotin, E., Ticoll, A., Cheung, W. A., Zhang, X. Y., Dickman, C. T., Fulton, D. L., Lim, J. S., Schnabl, J. M., Ramos, O. H., Vasseur-Cognet, M., de Leeuw, C. N., Simpson, E. M., Ryffel, G. U., Lam, E. W., Kist, R., Wilson, M. S., Marco-Ferreres, R., Brosens, J. J., Beccari, L. L., Bovolenta, P., Benayoun, B. A., Monteiro, L. J., Schwenen, H. D., Grontved, L., Wederell, E., Mandrup, S., Veitia, R. A., Chakravarthy, H., Hoodless, P. A., Mancarelli, M. M., Torbett, B. E., Banham, A. H., Reddy, S. P., Cullum, R. L., Liedtke, M., Tschan, M. P., Vaz, M., Rizzino, A., Zannini, M., Frietze, S., Farnham, P. J., Eijkelenboom, A., Brown, P. J., Laperriere, D., Leprince, D., de Cristofaro, T., Prince, K. L., Putker, M., del Peso, L., Camenisch, G., Wenger, R. H., Mikula, M., Rozendaal, M., Mader, S., Ostrowski, J., Rhodes, S. J., Van Rechem, C., Boulay, G., Olechnowicz, S. W., Breslin, M. B., Lan, M. S., Nanan, K. K., Wegner, M., Hou, J., Mullen, R. D., Colvin, S. C., Noy, P. J., Webb, C. F., Witek, M. E., Ferrell, S., Daniel, J. M., Park, J., Waldman, S. A., Peet, D. J., Taggart, M., Jayaraman, P., Karrich, J. J., Blom, B., Vesuna, F., O'Geen, H., Sun, Y., Gronostajski, R. M., Woodcroft, M. W., Hough, M. R., Chen, E., Europe-Finner, G. N., Karolczak-Bayatti, M., Bailey, J., Hankinson, O., Raman, V., LeBrun, D. P., Biswal, S., Harvey, C. J., DeBruyne, J. P., Hogenesch, J. B., Hevner, R. F., Heligon, C., Luo, X. M., Blank, M. C., Millen, K. J., Sharlin, D. S., Forrest, D., Dahlman-Wright, K., Zhao, C., Mishima, Y., Sinha, S., Chakrabarti, R., Portales-Casamar, E., Sladek, F. M., Bradley, P. H., Wasserman, W. W. 2012; 13 (3)

    Abstract

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.

    View details for DOI 10.1186/gb-2012-13-3-r24

    View details for Web of Science ID 000308544200009

    View details for PubMedID 22458515

  • Rapid activation of the bivalent gene Sox21 requires displacement of multiple layers of gene-silencing machinery FASEB JOURNAL Chakravarthy, H., Ormsbee, B. D., Mallanna, S. K., Rizzino, A. 2011; 25 (1): 206-218

    Abstract

    The rapid formation of numerous tissues during development is highly dependent on the swift activation of key developmental regulators. Recent studies indicate that many key regulatory genes are repressed in embryonic stem cells (ESCs), yet poised for rapid activation due to the presence of both activating (H3K4 trimethylation) and repressive (H3K27 trimethylation) histone modifications (bivalent genes). However, little is known about bivalent gene regulation. In this study, we investigated the regulation of the bivalent gene Sox21, which is activated rapidly when ESCs differentiate in response to increases in Sox2. Chromatin immunoprecipitation demonstrated that prior to differentiation, the Sox21 gene is bound by a complex array of repressive and activating transcriptional machinery. Upon activation, all identified repressive machinery and histone modifications associated with the gene are lost, but the activating modifications and transcriptional machinery are retained. Notably, these changes do not occur when ESCs differentiate in response to retinoic acid. Moreover, ESCs lacking a functional PRC2 complex fail to activate this gene, apparently due to its association with other repressive complexes. Together, these findings suggest that bivalent genes, such as Sox21, are silenced by a complex set of redundant repressive machinery, which exit rapidly in response to appropriate differentiation signals.

    View details for DOI 10.1096/fj.10-166926

    View details for Web of Science ID 000285869500019

    View details for PubMedID 20876214

  • Comparison of ras-responsive gene enhancers in pancreatic tumor cells that express either wild-type or mutant K-ras BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Wilder, P. J., Chakravarthy, H., Hollingsworth, M. A., Rizzino, A. 2009; 381 (4): 706-711

    Abstract

    There is a pressing need for new therapies to treat pancreatic cancer. In principle, this could be achieved by taking advantage of signaling pathways that are active in tumor, but not normal, cells. The work described in this study set out to determine whether the activities of three enhancers, which have been reported to be highly responsive to activated ras, differ in pancreatic tumor cells that express wild-type versus constitutively active mutant forms of K-ras. Surprisingly, the three enhancers are active in four different pancreatic tumor cell lines that express either normal K-ras gene or mutant K-ras. Moreover, reducing the concentration of serum in the growth medium from 10% to 0.5% had relatively little effect on the strength of any of the enhancers, although it drastically affected cell growth. Importantly, our studies also indicate that MEK is active in pancreatic tumor cells that possess wild-type as well as mutant K-ras, even when cultured in medium that severely limits cell growth. These findings support the hypothesis that the Ras/Raf/Mek/Erk pathway may be constitutively active even in pancreatic tumor cells that express wild-type K-ras.

    View details for DOI 10.1016/j.bbrc.2009.02.126

    View details for Web of Science ID 000264929400048

    View details for PubMedID 19254697

  • Identification of DPPA4 and other genes as putative Sox2 : Oct-3/4 target genes using a combination of in silico analysis and transcription-based assays JOURNAL OF CELLULAR PHYSIOLOGY Chakravarthy, H., Boer, B., Desler, M., Mallanna, S. K., McKeithan, T. W., Rizzino, A. 2008; 216 (3): 651-662

    Abstract

    Sox2 and Oct-3/4 function as master regulators during mammalian embryogenesis, where they are believed to regulate a critical gene regulatory network by cooperatively binding to DNA regulatory regions composed of adjacent HMG and POU motifs (HMG/POU cassettes). Previous studies have identified seven genes that contain highly active HMG/POU cassettes (referred to as Sox2:Oct-3/4 target genes). Importantly, nearly all known Sox2:Oct-3/4 target genes appear to be essential for embryogenesis. Recent genome-wide ChIP-chip studies identified over 300 genes that are co-occupied by Sox2 and Oct-3/4, which suggests that most Sox2:Oct-3/4 target genes remain to be identified. The work described here used a 3-step strategy for identifying additional Sox2:Oct-3/4 target genes. First, we employed in silico analysis to search for putative HMG/POU cassettes in 50 genes reported to be co-occupied by Sox2 and Oct-3/4 in embryonic stem cells. We identified 39 genes that contain putative HMG/POU cassettes. Next, we tested the activity of seven of the putative HMG/POU cassettes in a transcription-based assay and determined that nearly all are functional. Finally, as a proof-of-principle, we tested one of the seven cassettes (DPPA4) in the context of its endogenous promoter using a promoter/reporter gene construct. DPPA4 was tested in part because it was shown recently to play an important role in ES cell self-renewal. We determined that the 5' flanking region of the DPPA4 gene contains a functional HMG/POU cassette and behaves as a Sox2:Oct-3/4 target gene. Finally, we used a transcription-based assay to help develop a refined consensus sequence for HMG/POU cassettes.

    View details for DOI 10.1002/jcp.21440

    View details for Web of Science ID 000258273400010

    View details for PubMedID 18366076

  • Elevating the levels of Sox2 in embryonal carcinoma cells and embryonic stem cells inhibits the expression of Sox2 : Oct-3/4 target genes NUCLEIC ACIDS RESEARCH Boer, B., Kopp, J., Mallanna, S., Desler, M., Chakravarthy, H., Wilder, P. J., Bernadt, C., Rizzino, A. 2007; 35 (6): 1773-1786

    Abstract

    Recent studies have identified large sets of genes in embryonic stem and embryonal carcinoma cells that are associated with the transcription factors Sox2 and Oct-3/4. Other studies have shown that Sox2 and Oct-3/4 work together cooperatively to stimulate the transcription of their own genes as well as a network of genes required for embryogenesis. Moreover, small changes in the levels of Sox2:Oct-3/4 target genes alter the fate of stem cells. Although positive feedforward and feedback loops have been proposed to explain the activation of these genes, little is known about the mechanisms that prevent their overexpression. Here, we demonstrate that elevating Sox2 levels inhibits the endogenous expression of five Sox2:Oct-3/4 target genes. In addition, we show that Sox2 repression is dependent on the binding sites for Sox2 and Oct-3/4. We also demonstrate that inhibition is dependent on the C-terminus of Sox2, which contains its transactivation domain. Finally, our studies argue that overexpression of neither Oct-3/4 nor Nanog broadly inhibits Sox2:Oct-3/4 target genes. Collectively, these studies provide new insights into the diversity of mechanisms that control Sox2:Oct-3/4 target genes and argue that Sox2 functions as a molecular rheostat for the control of a key transcriptional regulatory network.

    View details for DOI 10.1093/nar/gkm059

    View details for Web of Science ID 000246123600013

    View details for PubMedID 17324942

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