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Tata, Purushothama Rao

Positions:

Assistant Professor of Cell Biology

Cell Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Regeneration Next Initiative

Regeneration Next Initiative
School of Medicine

Education:

Ph.D. 2011

Ph.D. — University of Ulm (Germany)

News:

Grants:

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

To define the role of Sox9 and Sox9+ Cells in Alveolar Homeostasis and Regeneration

Administered By
Cell Biology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
January 01, 2017
End Date
December 31, 2019

Publications:

ACTL6A Is Co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation, and Poor Prognosis.

Loss-of-function mutations in SWI/SNF chromatin-remodeling subunit genes are observed in many cancers, but an oncogenic role for SWI/SNF is not well established. Here, we reveal that ACTL6A, encoding an SWI/SNF subunit linked to stem cell and progenitor cell function, is frequently co-amplified and highly expressed together with the p53 family member p63 in head and neck squamous cell carcinoma (HNSCC). ACTL6A and p63 physically interact, cooperatively controlling a transcriptional program that promotes proliferation and suppresses differentiation, in part through activation of the Hippo-YAP pathway via regulators including WWC1. Ectopic ACTL6A/p63 expression promotes tumorigenesis, while ACTL6A expression and YAP activation are highly correlated in primary HNSCC and predict poor patient survival. Thus, ACTL6A and p63 collaborate as oncogenic drivers in HNSCC.

Authors
Saladi, SV; Ross, K; Karaayvaz, M; Tata, PR; Mou, H; Rajagopal, J; Ramaswamy, S; Ellisen, LW
MLA Citation
Saladi, SV, Ross, K, Karaayvaz, M, Tata, PR, Mou, H, Rajagopal, J, Ramaswamy, S, and Ellisen, LW. "ACTL6A Is Co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation, and Poor Prognosis." Cancer cell 31.1 (January 2017): 35-49.
PMID
28041841
Source
epmc
Published In
Cancer Cell
Volume
31
Issue
1
Publish Date
2017
Start Page
35
End Page
49
DOI
10.1016/j.ccell.2016.12.001

Cellular plasticity: 1712 to the present day.

Cell identity is a fundamental feature of cells. Tissues are often organized into cellular hierarchies characterized by progressive differentiation and developmental commitment. However, it is been historically evident that the cells of many organisms of various phyla, especially in the context of injury, exhibit remarkable plasticity in terms of their ability to convert into other cell types. Recent modern studies, using genetic lineage tracing, have demonstrated that many mature functional cells retain a potential to undergo lineage reversion (dedifferentiation) or to convert into cells of other more distant lineages (transdifferentiation) following injury. Similarly, mimicking progenitor cell transdetermination, stem cells can interconvert. These forms of plasticity may be essential for organismal survival, and are likely part and parcel of regeneration.

Authors
Tata, PR; Rajagopal, J
MLA Citation
Tata, PR, and Rajagopal, J. "Cellular plasticity: 1712 to the present day." Current opinion in cell biology 43 (December 2016): 46-54. (Review)
PMID
27485353
Source
epmc
Published In
Current Opinion in Cell Biology
Volume
43
Publish Date
2016
Start Page
46
End Page
54
DOI
10.1016/j.ceb.2016.07.005

Regulatory Circuits and Bi-directional Signaling between Stem Cells and Their Progeny.

Feedback signals from daughter cells to stem cells are well studied and known to provide important feedback cues. Emerging evidence shows that stem cells also send feedforward signals to their progeny. Complex circuits involving both negative and positive feedback and feedforward signals likely contribute to robust tissue maintenance and regeneration.

Authors
Tata, PR; Rajagopal, J
MLA Citation
Tata, PR, and Rajagopal, J. "Regulatory Circuits and Bi-directional Signaling between Stem Cells and Their Progeny." Cell stem cell 19.6 (December 2016): 686-689.
PMID
27912089
Source
epmc
Published In
Cell Stem Cell
Volume
19
Issue
6
Publish Date
2016
Start Page
686
End Page
689
DOI
10.1016/j.stem.2016.11.009

Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells.

Functional modeling of many adult epithelia is limited by the difficulty in maintaining relevant stem cell populations in culture. Here, we show that dual inhibition of SMAD signaling pathways enables robust expansion of primary epithelial basal cell populations. We find that TGFβ/BMP/SMAD pathway signaling is strongly activated in luminal and suprabasal cells of several epithelia, but suppressed in p63+ basal cells. In airway epithelium, SMAD signaling promotes differentiation, and its inhibition leads to stem cell hyperplasia. Using dual SMAD signaling inhibition in a feeder-free culture system, we have been able to expand airway basal stem cells from multiple species. Expanded cells can produce functional airway epithelium physiologically responsive to clinically relevant drugs, such as CFTR modulators. This approach is effective for the clonal expansion of single human cells and for basal cell populations from epithelial tissues from all three germ layers and therefore may be broadly applicable for modeling of epithelia.

Authors
Mou, H; Vinarsky, V; Tata, PR; Brazauskas, K; Choi, SH; Crooke, AK; Zhang, B; Solomon, GM; Turner, B; Bihler, H; Harrington, J; Lapey, A; Channick, C; Keyes, C; Freund, A; Artandi, S; Mense, M; Rowe, S; Engelhardt, JF; Hsu, Y-C; Rajagopal, J
MLA Citation
Mou, H, Vinarsky, V, Tata, PR, Brazauskas, K, Choi, SH, Crooke, AK, Zhang, B, Solomon, GM, Turner, B, Bihler, H, Harrington, J, Lapey, A, Channick, C, Keyes, C, Freund, A, Artandi, S, Mense, M, Rowe, S, Engelhardt, JF, Hsu, Y-C, and Rajagopal, J. "Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells." Cell stem cell 19.2 (August 2016): 217-231.
PMID
27320041
Source
epmc
Published In
Cell Stem Cell
Volume
19
Issue
2
Publish Date
2016
Start Page
217
End Page
231
DOI
10.1016/j.stem.2016.05.012

Parent stem cells can serve as niches for their daughter cells.

Stem cells integrate inputs from multiple sources. Stem cell niches provide signals that promote stem cell maintenance, while differentiated daughter cells are known to provide feedback signals to regulate stem cell replication and differentiation. Recently, stem cells have been shown to regulate themselves using an autocrine mechanism. The existence of a 'stem cell niche' was first postulated by Schofield in 1978 to define local environments necessary for the maintenance of haematopoietic stem cells. Since then, an increasing body of work has focused on defining stem cell niches. Yet little is known about how progenitor cell and differentiated cell numbers and proportions are maintained. In the airway epithelium, basal cells function as stem/progenitor cells that can both self-renew and produce differentiated secretory cells and ciliated cells. Secretory cells also act as transit-amplifying cells that eventually differentiate into post-mitotic ciliated cells . Here we describe a mode of cell regulation in which adult mammalian stem/progenitor cells relay a forward signal to their own progeny. Surprisingly, this forward signal is shown to be necessary for daughter cell maintenance. Using a combination of cell ablation, lineage tracing and signalling pathway modulation, we show that airway basal stem/progenitor cells continuously supply a Notch ligand to their daughter secretory cells. Without these forward signals, the secretory progenitor cell pool fails to be maintained and secretory cells execute a terminal differentiation program and convert into ciliated cells. Thus, a parent stem/progenitor cell can serve as a functional daughter cell niche.

Authors
Pardo-Saganta, A; Tata, PR; Law, BM; Saez, B; Chow, RD-W; Prabhu, M; Gridley, T; Rajagopal, J
MLA Citation
Pardo-Saganta, A, Tata, PR, Law, BM, Saez, B, Chow, RD-W, Prabhu, M, Gridley, T, and Rajagopal, J. "Parent stem cells can serve as niches for their daughter cells." Nature 523.7562 (July 6, 2015): 597-601.
PMID
26147083
Source
epmc
Published In
Nature
Volume
523
Issue
7562
Publish Date
2015
Start Page
597
End Page
601
DOI
10.1038/nature14553

Injury induces direct lineage segregation of functionally distinct airway basal stem/progenitor cell subpopulations.

Following injury, stem cells restore normal tissue architecture by producing the proper number and proportions of differentiated cells. Current models of airway epithelial regeneration propose that distinct cytokeratin 8-expressing progenitor cells, arising from p63(+) basal stem cells, subsequently differentiate into secretory and ciliated cell lineages. We now show that immediately following injury, discrete subpopulations of p63(+) airway basal stem/progenitor cells themselves express Notch pathway components associated with either secretory or ciliated cell fate commitment. One basal cell population displays intracellular Notch2 activation and directly generates secretory cells; the other expresses c-myb and directly yields ciliated cells. Furthermore, disrupting Notch ligand activity within the basal cell population at large disrupts the normal pattern of lineage segregation. These non-cell-autonomous effects demonstrate that effective airway epithelial regeneration requires intercellular communication within the broader basal stem/progenitor cell population. These findings have broad implications for understanding epithelial regeneration and stem cell heterogeneity.

Authors
Pardo-Saganta, A; Law, BM; Tata, PR; Villoria, J; Saez, B; Mou, H; Zhao, R; Rajagopal, J
MLA Citation
Pardo-Saganta, A, Law, BM, Tata, PR, Villoria, J, Saez, B, Mou, H, Zhao, R, and Rajagopal, J. "Injury induces direct lineage segregation of functionally distinct airway basal stem/progenitor cell subpopulations." Cell stem cell 16.2 (February 2015): 184-197.
PMID
25658372
Source
epmc
Published In
Cell Stem Cell
Volume
16
Issue
2
Publish Date
2015
Start Page
184
End Page
197
DOI
10.1016/j.stem.2015.01.002

TBX3 Directs Cell-Fate Decision toward Mesendoderm

Authors
Weidgang, CE; Russell, R; Tata, PR; Kühl, SJ; Illing, A; Müller, M; Lin, Q; Brunner, C; Boeckers, TM; Bauer, K; Kartikasari, AER; Guo, Y; Radenz, M; Bernemann, C; Weiß, M; Seufferlein, T; Zenke, M; Iacovino, M; Kyba, M; Schöler, HR; Kühl, M; Liebau, S; Kleger, A
MLA Citation
Weidgang, CE, Russell, R, Tata, PR, Kühl, SJ, Illing, A, Müller, M, Lin, Q, Brunner, C, Boeckers, TM, Bauer, K, Kartikasari, AER, Guo, Y, Radenz, M, Bernemann, C, Weiß, M, Seufferlein, T, Zenke, M, Iacovino, M, Kyba, M, Schöler, HR, Kühl, M, Liebau, S, and Kleger, A. "TBX3 Directs Cell-Fate Decision toward Mesendoderm." Stem Cell Reports 2.5 (May 2014): 747-747.
Source
crossref
Published In
Stem Cell Reports
Volume
2
Issue
5
Publish Date
2014
Start Page
747
End Page
747
DOI
10.1016/j.stemcr.2014.04.011

Airway-specific inducible transgene expression using aerosolized doxycycline.

Tissue-specific transgene expression using tetracycline (tet)-regulated promoter/operator elements has been used to revolutionize our understanding of cellular and molecular processes. However, because most tet-regulated mouse strains use promoters of genes expressed in multiple tissues, to achieve exclusive expression in an organ of interest is often impossible. Indeed, in the extreme case, unwanted transgene expression in other organ systems causes lethality and precludes the study of the transgene in the actual organ of interest. Here, we describe a novel approach to activating tet-inducible transgene expression solely in the airway by administering aerosolized doxycycline. By optimizing the dose and duration of aerosolized doxycycline exposure in mice possessing a ubiquitously expressed Rosa26 promoter-driven reverse tet-controlled transcriptional activator (rtTA) element, we induce transgene expression exclusively in the airways. We detect no changes in the cellular composition or proliferative behavior of airway cells. We used this newly developed method to achieve airway basal stem cell-specific transgene expression using a cytokeratin 5 (also known as keratin 5)-driven rtTA driver line to induce Notch pathway activation. We observed a more robust mucous metaplasia phenotype than in mice receiving doxycycline systemically. In addition, unwanted phenotypes outside of the lung that were evident when doxycycline was received systemically were now absent. Thus, our approach allows for rapid and efficient airway-specific transgene expression. After the careful strain by strain titration of the dose and timing of doxycycline inhalation, a suite of preexisting transgenic mice can now be used to study airway biology specifically in cases where transient transgene expression is sufficient to induce a phenotype.

Authors
Tata, PR; Pardo-Saganta, A; Prabhu, M; Vinarsky, V; Law, BM; Fontaine, BA; Tager, AM; Rajagopal, J
MLA Citation
Tata, PR, Pardo-Saganta, A, Prabhu, M, Vinarsky, V, Law, BM, Fontaine, BA, Tager, AM, and Rajagopal, J. "Airway-specific inducible transgene expression using aerosolized doxycycline." American journal of respiratory cell and molecular biology 49.6 (December 2013): 1048-1056.
PMID
23848320
Source
epmc
Published In
American journal of respiratory cell and molecular biology
Volume
49
Issue
6
Publish Date
2013
Start Page
1048
End Page
1056
DOI
10.1165/rcmb.2012-0412oc

Dedifferentiation of committed epithelial cells into stem cells in vivo.

Cellular plasticity contributes to the regenerative capacity of plants, invertebrates, teleost fishes and amphibians. In vertebrates, differentiated cells are known to revert into replicating progenitors, but these cells do not persist as stable stem cells. Here we present evidence that differentiated airway epithelial cells can revert into stable and functional stem cells in vivo. After the ablation of airway stem cells, we observed a surprising increase in the proliferation of committed secretory cells. Subsequent lineage tracing demonstrated that the luminal secretory cells had dedifferentiated into basal stem cells. Dedifferentiated cells were morphologically indistinguishable from stem cells and they functioned as well as their endogenous counterparts in repairing epithelial injury. Single secretory cells clonally dedifferentiated into multipotent stem cells when they were cultured ex vivo without basal stem cells. By contrast, direct contact with a single basal stem cell was sufficient to prevent secretory cell dedifferentiation. In analogy to classical descriptions of amphibian nuclear reprogramming, the propensity of committed cells to dedifferentiate is inversely correlated to their state of maturity. This capacity of committed cells to dedifferentiate into stem cells may have a more general role in the regeneration of many tissues and in multiple disease states, notably cancer.

Authors
Tata, PR; Mou, H; Pardo-Saganta, A; Zhao, R; Prabhu, M; Law, BM; Vinarsky, V; Cho, JL; Breton, S; Sahay, A; Medoff, BD; Rajagopal, J
MLA Citation
Tata, PR, Mou, H, Pardo-Saganta, A, Zhao, R, Prabhu, M, Law, BM, Vinarsky, V, Cho, JL, Breton, S, Sahay, A, Medoff, BD, and Rajagopal, J. "Dedifferentiation of committed epithelial cells into stem cells in vivo." Nature 503.7475 (November 6, 2013): 218-223.
PMID
24196716
Source
epmc
Published In
Nature
Volume
503
Issue
7475
Publish Date
2013
Start Page
218
End Page
223
DOI
10.1038/nature12777

Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO3 as a functional transcriptional target.

The NKX2-1 transcription factor, a regulator of normal lung development, is the most significantly amplified gene in human lung adenocarcinoma. To study the transcriptional impact of NKX2-1 amplification, we generated an expression signature associated with NKX2-1 amplification in human lung adenocarcinoma and analyzed DNA-binding sites of NKX2-1 by genome-wide chromatin immunoprecipitation. Integration of these expression and cistromic analyses identified LMO3, itself encoding a transcription regulator, as a candidate direct transcriptional target of NKX2-1. Further cistromic and overexpression analyses indicated that NKX2-1 can cooperate with the forkhead box transcription factor FOXA1 to regulate LMO3 gene expression. RNAi analysis of NKX2-1-amplified cells compared with nonamplified cells demonstrated that LMO3 mediates cell survival downstream from NKX2-1. Our findings provide new insight into the transcriptional regulatory network of NKX2-1 and suggest that LMO3 is a transcriptional signal transducer in NKX2-1-amplified lung adenocarcinomas.

Authors
Watanabe, H; Francis, JM; Woo, MS; Etemad, B; Lin, W; Fries, DF; Peng, S; Snyder, EL; Tata, PR; Izzo, F; Schinzel, AC; Cho, J; Hammerman, PS; Verhaak, RG; Hahn, WC; Rajagopal, J; Jacks, T; Meyerson, M
MLA Citation
Watanabe, H, Francis, JM, Woo, MS, Etemad, B, Lin, W, Fries, DF, Peng, S, Snyder, EL, Tata, PR, Izzo, F, Schinzel, AC, Cho, J, Hammerman, PS, Verhaak, RG, Hahn, WC, Rajagopal, J, Jacks, T, and Meyerson, M. "Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO3 as a functional transcriptional target." Genes & development 27.2 (January 15, 2013): 197-210.
PMID
23322301
Source
epmc
Published In
Genes & development
Volume
27
Issue
2
Publish Date
2013
Start Page
197
End Page
210
DOI
10.1101/gad.203208.112

TBX3 Directs Cell-Fate Decision toward Mesendoderm.

Cell-fate decisions and pluripotency are dependent on networks of key transcriptional regulators. Recent reports demonstrated additional functions of pluripotency-associated factors during early lineage commitment. The T-box transcription factor TBX3 has been implicated in regulating embryonic stem cell self-renewal and cardiogenesis. Here, we show that TBX3 is dynamically expressed during specification of the mesendoderm lineages in differentiating embryonic stem cells (ESCs) in vitro and in developing mouse and Xenopus embryos in vivo. Forced TBX3 expression in ESCs promotes mesendoderm specification by directly activating key lineage specification factors and indirectly by enhancing paracrine Nodal/Smad2 signaling. TBX3 loss-of-function analyses in the Xenopus underline its requirement for mesendoderm lineage commitment. Moreover, we uncovered a functional redundancy between TBX3 and Tbx2 during Xenopus gastrulation. Taken together, we define further facets of TBX3 actions and map TBX3 as an upstream regulator of the mesendoderm transcriptional program during gastrulation.

Authors
Weidgang, CE; Russell, R; Tata, PR; Kühl, SJ; Illing, A; Müller, M; Lin, Q; Brunner, C; Boeckers, TM; Bauer, K; Kartikasari, AER; Guo, Y; Radenz, M; Bernemann, C; Weiß, M; Seufferlein, T; Zenke, M; Iacovino, M; Kyba, M; Schöler, HR; Kühl, M; Liebau, S; Kleger, A
MLA Citation
Weidgang, CE, Russell, R, Tata, PR, Kühl, SJ, Illing, A, Müller, M, Lin, Q, Brunner, C, Boeckers, TM, Bauer, K, Kartikasari, AER, Guo, Y, Radenz, M, Bernemann, C, Weiß, M, Seufferlein, T, Zenke, M, Iacovino, M, Kyba, M, Schöler, HR, Kühl, M, Liebau, S, and Kleger, A. "TBX3 Directs Cell-Fate Decision toward Mesendoderm." Stem cell reports 1.3 (January 2013): 248-265.
PMID
24319661
Source
epmc
Published In
Stem Cell Reports
Volume
1
Issue
3
Publish Date
2013
Start Page
248
End Page
265
DOI
10.1016/j.stemcr.2013.08.002

Identification of a novel epigenetic regulatory region within the pluripotency associated microRNA cluster, EEmiRC.

The miR-290 cluster is expressed in embryonic stem cells (ESCs) and is important for the maintenance of pluripotency, but little is known about the mechanisms regulating the early embryonic microRNA cluster (EEmiRC) expression. Here we report the identification of a 332-bp intragenic enhancer (IE) able to modulate the transcription of the mouse EEmiRC locus, presumably through binding of transcription modulators like Oct3/4, Sox2 and CTCF. This IE also contains a CpG island showing a differential pattern of DNA and histone methylation marks during differentiation of ESCs, which places EEmiRC in a novel regulatory feedback loop with DNA methylases. Deletion of IE significantly reduced the transcription of the EEmiRC, further proving the importance of this region in regulating the expression of EEmiRC.

Authors
Tata, PR; Tata, NR; Kühl, M; Sirbu, IO
MLA Citation
Tata, PR, Tata, NR, Kühl, M, and Sirbu, IO. "Identification of a novel epigenetic regulatory region within the pluripotency associated microRNA cluster, EEmiRC." Nucleic acids research 39.9 (May 2011): 3574-3581.
PMID
21247880
Source
epmc
Published In
Nucleic Acids Research
Volume
39
Issue
9
Publish Date
2011
Start Page
3574
End Page
3581
DOI
10.1093/nar/gkq1344
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