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2. Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites

Author

Patzak, Melanie S., Kari, Vijayalakshmi, Patil, Shilpa, Hamdan, Feda H., Goetze, Robert G., Brunner, Marius, Gaedcke, Jochen, Kitz, Julia, Jodrell, Duncan I., Richards, Frances M., Pilarsky, Christian, Gruetzmann, Robert, Rümmele, Petra, Knösel, Thomas, Hessmann, Elisabeth, Ellenrieder, Volker, Johnsen, Steven A., and Neesse, Albrecht

Published
2019
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6. Supplementary Table 8 from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, primary, Kopp, Waltraut, primary, Kari, Vijayalakshmi, primary, Urbach, Laura, primary, Wang, Xin, primary, Küffer, Stefan, primary, Bohnenberger, Hanibal, primary, Spyropoulou, Dimitra, primary, Zhang, Zhe, primary, Versemann, Lennart, primary, Bösherz, Mark Sebastian, primary, Brunner, Marius, primary, Gaedcke, Jochen, primary, Ströbel, Philipp, primary, Zhang, Jin-San, primary, Neesse, Albrecht, primary, Ellenrieder, Volker, primary, Singh, Shiv K., primary, Johnsen, Steven A., primary, and Hessmann, Elisabeth, primary

Published
2023
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7. Supplementary Figure 6 from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, primary, Kopp, Waltraut, primary, Kari, Vijayalakshmi, primary, Urbach, Laura, primary, Wang, Xin, primary, Küffer, Stefan, primary, Bohnenberger, Hanibal, primary, Spyropoulou, Dimitra, primary, Zhang, Zhe, primary, Versemann, Lennart, primary, Bösherz, Mark Sebastian, primary, Brunner, Marius, primary, Gaedcke, Jochen, primary, Ströbel, Philipp, primary, Zhang, Jin-San, primary, Neesse, Albrecht, primary, Ellenrieder, Volker, primary, Singh, Shiv K., primary, Johnsen, Steven A., primary, and Hessmann, Elisabeth, primary

Published
2023
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8. Supplementary Figure 2 from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, primary, Kopp, Waltraut, primary, Kari, Vijayalakshmi, primary, Urbach, Laura, primary, Wang, Xin, primary, Küffer, Stefan, primary, Bohnenberger, Hanibal, primary, Spyropoulou, Dimitra, primary, Zhang, Zhe, primary, Versemann, Lennart, primary, Bösherz, Mark Sebastian, primary, Brunner, Marius, primary, Gaedcke, Jochen, primary, Ströbel, Philipp, primary, Zhang, Jin-San, primary, Neesse, Albrecht, primary, Ellenrieder, Volker, primary, Singh, Shiv K., primary, Johnsen, Steven A., primary, and Hessmann, Elisabeth, primary

Published
2023
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9. Supplementary Figure 4 from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, primary, Kopp, Waltraut, primary, Kari, Vijayalakshmi, primary, Urbach, Laura, primary, Wang, Xin, primary, Küffer, Stefan, primary, Bohnenberger, Hanibal, primary, Spyropoulou, Dimitra, primary, Zhang, Zhe, primary, Versemann, Lennart, primary, Bösherz, Mark Sebastian, primary, Brunner, Marius, primary, Gaedcke, Jochen, primary, Ströbel, Philipp, primary, Zhang, Jin-San, primary, Neesse, Albrecht, primary, Ellenrieder, Volker, primary, Singh, Shiv K., primary, Johnsen, Steven A., primary, and Hessmann, Elisabeth, primary

Published
2023
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10. Supplementary Data from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, primary, Kopp, Waltraut, primary, Kari, Vijayalakshmi, primary, Urbach, Laura, primary, Wang, Xin, primary, Küffer, Stefan, primary, Bohnenberger, Hanibal, primary, Spyropoulou, Dimitra, primary, Zhang, Zhe, primary, Versemann, Lennart, primary, Bösherz, Mark Sebastian, primary, Brunner, Marius, primary, Gaedcke, Jochen, primary, Ströbel, Philipp, primary, Zhang, Jin-San, primary, Neesse, Albrecht, primary, Ellenrieder, Volker, primary, Singh, Shiv K., primary, Johnsen, Steven A., primary, and Hessmann, Elisabeth, primary

Published
2023
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11. Supplementary Figure 1 from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, primary, Kopp, Waltraut, primary, Kari, Vijayalakshmi, primary, Urbach, Laura, primary, Wang, Xin, primary, Küffer, Stefan, primary, Bohnenberger, Hanibal, primary, Spyropoulou, Dimitra, primary, Zhang, Zhe, primary, Versemann, Lennart, primary, Bösherz, Mark Sebastian, primary, Brunner, Marius, primary, Gaedcke, Jochen, primary, Ströbel, Philipp, primary, Zhang, Jin-San, primary, Neesse, Albrecht, primary, Ellenrieder, Volker, primary, Singh, Shiv K., primary, Johnsen, Steven A., primary, and Hessmann, Elisabeth, primary

Published
2023
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12. Data from Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism

Author

Mishra, Vivek Kumar, primary, Subramaniam, Malayannan, primary, Kari, Vijayalakshmi, primary, Pitel, Kevin S., primary, Baumgart, Simon J., primary, Naylor, Ryan M., primary, Nagarajan, Sankari, primary, Wegwitz, Florian, primary, Ellenrieder, Volker, primary, Hawse, John R., primary, and Johnsen, Steven A., primary

Published
2023
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13. Supplementary Figure 5 from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, primary, Kopp, Waltraut, primary, Kari, Vijayalakshmi, primary, Urbach, Laura, primary, Wang, Xin, primary, Küffer, Stefan, primary, Bohnenberger, Hanibal, primary, Spyropoulou, Dimitra, primary, Zhang, Zhe, primary, Versemann, Lennart, primary, Bösherz, Mark Sebastian, primary, Brunner, Marius, primary, Gaedcke, Jochen, primary, Ströbel, Philipp, primary, Zhang, Jin-San, primary, Neesse, Albrecht, primary, Ellenrieder, Volker, primary, Singh, Shiv K., primary, Johnsen, Steven A., primary, and Hessmann, Elisabeth, primary

Published
2023
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14. Supplementary Table 7 from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, primary, Kopp, Waltraut, primary, Kari, Vijayalakshmi, primary, Urbach, Laura, primary, Wang, Xin, primary, Küffer, Stefan, primary, Bohnenberger, Hanibal, primary, Spyropoulou, Dimitra, primary, Zhang, Zhe, primary, Versemann, Lennart, primary, Bösherz, Mark Sebastian, primary, Brunner, Marius, primary, Gaedcke, Jochen, primary, Ströbel, Philipp, primary, Zhang, Jin-San, primary, Neesse, Albrecht, primary, Ellenrieder, Volker, primary, Singh, Shiv K., primary, Johnsen, Steven A., primary, and Hessmann, Elisabeth, primary

Published
2023
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15. Data from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, primary, Kopp, Waltraut, primary, Kari, Vijayalakshmi, primary, Urbach, Laura, primary, Wang, Xin, primary, Küffer, Stefan, primary, Bohnenberger, Hanibal, primary, Spyropoulou, Dimitra, primary, Zhang, Zhe, primary, Versemann, Lennart, primary, Bösherz, Mark Sebastian, primary, Brunner, Marius, primary, Gaedcke, Jochen, primary, Ströbel, Philipp, primary, Zhang, Jin-San, primary, Neesse, Albrecht, primary, Ellenrieder, Volker, primary, Singh, Shiv K., primary, Johnsen, Steven A., primary, and Hessmann, Elisabeth, primary

Published
2023
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16. Supplementary Figure 7 from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, primary, Kopp, Waltraut, primary, Kari, Vijayalakshmi, primary, Urbach, Laura, primary, Wang, Xin, primary, Küffer, Stefan, primary, Bohnenberger, Hanibal, primary, Spyropoulou, Dimitra, primary, Zhang, Zhe, primary, Versemann, Lennart, primary, Bösherz, Mark Sebastian, primary, Brunner, Marius, primary, Gaedcke, Jochen, primary, Ströbel, Philipp, primary, Zhang, Jin-San, primary, Neesse, Albrecht, primary, Ellenrieder, Volker, primary, Singh, Shiv K., primary, Johnsen, Steven A., primary, and Hessmann, Elisabeth, primary

Published
2023
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17. Supplementary Figures 1-3 from Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism

Author

Mishra, Vivek Kumar, primary, Subramaniam, Malayannan, primary, Kari, Vijayalakshmi, primary, Pitel, Kevin S., primary, Baumgart, Simon J., primary, Naylor, Ryan M., primary, Nagarajan, Sankari, primary, Wegwitz, Florian, primary, Ellenrieder, Volker, primary, Hawse, John R., primary, and Johnsen, Steven A., primary

Published
2023
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18. Supplementary Figure 3 from EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, primary, Kopp, Waltraut, primary, Kari, Vijayalakshmi, primary, Urbach, Laura, primary, Wang, Xin, primary, Küffer, Stefan, primary, Bohnenberger, Hanibal, primary, Spyropoulou, Dimitra, primary, Zhang, Zhe, primary, Versemann, Lennart, primary, Bösherz, Mark Sebastian, primary, Brunner, Marius, primary, Gaedcke, Jochen, primary, Ströbel, Philipp, primary, Zhang, Jin-San, primary, Neesse, Albrecht, primary, Ellenrieder, Volker, primary, Singh, Shiv K., primary, Johnsen, Steven A., primary, and Hessmann, Elisabeth, primary

Published
2023
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23. EZH2 Regulates Pancreatic Cancer Subtype Identity and Tumor Progression via Transcriptional Repression of GATA6

Author

Patil, Shilpa, primary, Steuber, Benjamin, additional, Kopp, Waltraut, additional, Kari, Vijayalakshmi, additional, Urbach, Laura, additional, Wang, Xin, additional, Küffer, Stefan, additional, Bohnenberger, Hanibal, additional, Spyropoulou, Dimitra, additional, Zhang, Zhe, additional, Versemann, Lennart, additional, Bösherz, Mark Sebastian, additional, Brunner, Marius, additional, Gaedcke, Jochen, additional, Ströbel, Philipp, additional, Zhang, Jin-San, additional, Neesse, Albrecht, additional, Ellenrieder, Volker, additional, Singh, Shiv K., additional, Johnsen, Steven A., additional, and Hessmann, Elisabeth, additional

Published
2020
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24. Dipeptidyl peptidase 9 triggers BRCA2 degradation by the N-degron pathway to promote DNA-damage repair

Author

Silva-Garcia, Maria, primary, Bolgi, Oguz, additional, Ross, Breyan, additional, Pilla, Esther, additional, Kari, Vijayalakshmi, additional, Killisch, Markus, additional, Stark, Nadine, additional, Lenz, Christof, additional, Spitzner, Melanie, additional, Gorrell, Mark D., additional, Grade, Marian, additional, Urlaub, Henning, additional, Dobbelstein, Matthias, additional, Huber, Robert, additional, and Geiss-Friedlander, Ruth, additional

Published
2020
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26. A context-specific cardiac β-catenin and GATA4 interaction influences TCF7L2 occupancy and remodels chromatin driving disease progression in the adult heart

Author

Iyer, Lavanya M, Nagarajan, Sankari, Woelfer, Monique, Schoger, Eric, Khadjeh, Sara, Zafiriou, Maria Patapia, Kari, Vijayalakshmi, Herting, Jonas, Pang, Sze Ting, Weber, Tobias, Rathjens, Franziska S, Fischer, Thomas H, Toischer, Karl, Hasenfuss, Gerd, Noack, Claudia, Johnsen, Steven A, and Zelarayán, Laura C

Subjects
Adult, Heart Failure, Mice, Knockout, Gene Expression Profiling, Myocardium, Gene regulation, Chromatin and Epigenetics, Mice, Transgenic, Chromatin Assembly and Disassembly, Chromatin, GATA4 Transcription Factor, Disease Progression, Animals, Humans, Myocytes, Cardiac, Transcription Factor 7-Like 2 Protein, Wnt Signaling Pathway, beta Catenin, Protein Binding
Abstract

Chromatin remodelling precedes transcriptional and structural changes in heart failure. A body of work suggests roles for the developmental Wnt signalling pathway in cardiac remodelling. Hitherto, there is no evidence supporting a direct role of Wnt nuclear components in regulating chromatin landscapes in this process. We show that transcriptionally active, nuclear, phosphorylated(p)Ser675-β-catenin and TCF7L2 are upregulated in diseased murine and human cardiac ventricles. We report that inducible cardiomyocytes (CM)-specific pSer675-β-catenin accumulation mimics the disease situation by triggering TCF7L2 expression. This enhances active chromatin, characterized by increased H3K27ac and TCF7L2 occupancies to cardiac developmental and remodelling genes in vivo. Accordingly, transcriptomic analysis of β-catenin stabilized hearts shows a strong recapitulation of cardiac developmental processes like cell cycling and cytoskeletal remodelling. Mechanistically, TCF7L2 co-occupies distal genomic regions with cardiac transcription factors NKX2–5 and GATA4 in stabilized-β-catenin hearts. Validation assays revealed a previously unrecognized function of GATA4 as a cardiac repressor of the TCF7L2/β-catenin complex in vivo, thereby defining a transcriptional switch controlling disease progression. Conversely, preventing β-catenin activation post-pressure-overload results in a downregulation of these novel TCF7L2-targets and rescues cardiac function. Thus, we present a novel role for TCF7L2/β-catenin in CMs-specific chromatin modulation, which could be exploited for manipulating the ubiquitous Wnt pathway.

Published
2018
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27. Egr2-guided histone H2B monoubiquitination is required for peripheral nervous system myelination

Author

Wüst, Hannah M, Wegener, Amélie, Fröb, Franziska, Hartwig, Anna C, Wegwitz, Florian, Kari, Vijayalakshmi, Schimmel, Margit, Tamm, Ernst R, Johnsen, Steven A, Wegner, Michael, and Sock, Elisabeth

Subjects
AcademicSubjects/SCI00010, Ubiquitin-Protein Ligases, Gene regulation, Chromatin and Epigenetics, Ubiquitination, Mice, Transgenic, Rats, Histones, Mice, HEK293 Cells, nervous system, Cell Line, Tumor, Peripheral Nervous System, Animals, Humans, Schwann Cells, ddc:610, Hereditary Sensory and Motor Neuropathy, Early Growth Response Protein 2
Abstract

Schwann cells are the nerve ensheathing cells of the peripheral nervous system. Absence, loss and malfunction of Schwann cells or their myelin sheaths lead to peripheral neuropathies such as Charcot-Marie-Tooth disease in humans. During Schwann cell development and myelination chromatin is dramatically modified. However, impact and functional relevance of these modifications are poorly understood. Here, we analyzed histone H2B monoubiquitination as one such chromatin modification by conditionally deleting the Rnf40 subunit of the responsible E3 ligase in mice. Rnf40-deficient Schwann cells were arrested immediately before myelination or generated abnormally thin, unstable myelin, resulting in a peripheral neuropathy characterized by hypomyelination and progressive axonal degeneration. By combining sequencing techniques with functional studies we show that H2B monoubiquitination does not influence global gene expression patterns, but instead ensures selective high expression of myelin and lipid biosynthesis genes and proper repression of immaturity genes. This requires the specific recruitment of the Rnf40-containing E3 ligase by Egr2, the central transcriptional regulator of peripheral myelination, to its target genes. Our study identifies histone ubiquitination as essential for Schwann cell myelination and unravels new disease-relevant links between chromatin modifications and transcription factors in the underlying regulatory network.

Published
2020

29. EZH2 controls PDAC plasticity by regulating differentiation genes

Author

Patil, Shilpa, primary, Najafova, Zeynab, additional, Kari, Vijayalakshmi, additional, Wang, Xin, additional, Bohnenberger, Hanibal, additional, Kopp, Waltraut, additional, Spitalieri, Jessica, additional, Neesse, Albrecht, additional, Ellenrieder, Volker, additional, Johnsen, Steven, additional, and Hessmann, Elisabeth, additional

Published
2019
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30. Loss ofCHD 1causes DNA repair defects and enhances prostate cancer therapeutic responsiveness

Author

Kari, Vijayalakshmi, primary, Mansour, Wael Yassin, additional, Raul, Sanjay Kumar, additional, Baumgart, Simon J, additional, Mund, Andreas, additional, Grade, Marian, additional, Sirma, Hüseyin, additional, Simon, Ronald, additional, Will, Hans, additional, Dobbelstein, Matthias, additional, Dikomey, Ekkehard, additional, and Johnsen, Steven A, additional

Published
2018
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33. Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4-and MYC-dependent manner

Author

Mishra, Vivek Kumar, Wegwitz, Florian, Kosinsky, Robyn Laura, Sen, Madhobi, Baumgartner, Roland, Wulff, Tanja, Siveke, Jens, Schildhaus, Hans-Ulrich, Najafova, Zeynab, Kari, Vijayalakshmi, Kohlhof, Hella, Hessmann, Elisabeth, and Johnsen, Steven A.

Subjects
Medizin
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a particularly dismal prognosis. Histone deacetylases (HDAC) are epigenetic modulators whose activity is frequently deregulated in various cancers including PDAC. In particular, class-I HDACs (HDAC 1, 2, 3 and 8) have been shown to play an important role in PDAC. In this study, we investigated the effects of the class Ispecific HDAC inhibitor (HDACi) 4SC-202 in multiple PDAC cell lines in promoting tumor cell differentiation. We show that 4SC-202 negatively affects TGF' signaling and inhibits TGF'-induced epithelial-tomesenchymal transition (EMT). Moreover, 4SC-202 markedly induced p21 (CDKN1A) expression and significantly attenuated cell proliferation. Mechanistically, genome-wide studies revealed that 4SC-202-induced genes were enriched for Bromodomaincontaining Protein-4 (BRD4) and MYC occupancy. BRD4, a well-characterized acetyllysine reader, has been shown to play a major role in regulating transcription of selected subsets of genes. Importantly, BRD4 and MYC are essential for the expression of a subgroup of genes induced by class-I HDACi. Taken together, our study uncovers a previously unknown role of BRD4 and MYC in eliciting the HDACimediated induction of a subset of genes and provides molecular insight into the mechanisms of HDACi action in PDAC. OA gold

Published
2017

37. Krüppel-like Transcription Factor KLF10 Suppresses TGFβ-Induced Epithelial-to-Mesenchymal Transition via a Negative Feedback Mechanism

Author

Mishra, Vivek Kumar, primary, Subramaniam, Malayannan, additional, Kari, Vijayalakshmi, additional, Pitel, Kevin S., additional, Baumgart, Simon J., additional, Naylor, Ryan M., additional, Nagarajan, Sankari, additional, Wegwitz, Florian, additional, Ellenrieder, Volker, additional, Hawse, John R., additional, and Johnsen, Steven A., additional

Published
2017
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38. BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells

Author

Nagarajan, Sankari, Bedi, Upasana, Budida, Anusha, Hamdan, Feda H., Mishra, Vivek Kumar, Najafova, Zeynab, Xie, Wanhua, Alawi, Malik, Indenbirken, Daniela, Knapp, Stefan, Chiang, Cheng-Ming, Grundhoff, Adam, Kari, Vijayalakshmi, Scheel, Christina H., Wegwitz, Florian, Johnsen, Steven A., Nagarajan, Sankari, Bedi, Upasana, Budida, Anusha, Hamdan, Feda H., Mishra, Vivek Kumar, Najafova, Zeynab, Xie, Wanhua, Alawi, Malik, Indenbirken, Daniela, Knapp, Stefan, Chiang, Cheng-Ming, Grundhoff, Adam, Kari, Vijayalakshmi, Scheel, Christina H., Wegwitz, Florian, and Johnsen, Steven A.

Abstract

Bromodomain-containing protein 4 (BRD4) is a member of the bromo- and extraterminal (BET) domain-containing family of epigenetic readers which is under intensive investigation as a target for anti-tumor therapy. BRD4 plays a central role in promoting the expression of select subsets of genes including many driven by oncogenic transcription factors and signaling pathways. However, the role of BRD4 and the effects of BET inhibitors in non-transformed cells remain mostly unclear. We demonstrate that BRD4 is required for the maintenance of a basal epithelial phenotype by regulating the expression of epithelial-specific genes including TP63 and Grainy Head-like transcription factor-3 (GRHL3) in non-transformed basal-like mammary epithelial cells. Moreover, BRD4 occupancy correlates with enhancer activity and enhancer RNA (eRNA) transcription. Motif analyses of cell context-specific BRD4-enriched regions predicted the involvement of FOXO transcription factors. Consistently, activation of FOXO1 function via inhibition of EGFR-AKT signaling promoted the expression of TP63 and GRHL3. Moreover, activation of Src kinase signaling and FOXO1 inhibition decreased the expression of FOXO/BRD4 target genes. Together, our findings support a function for BRD4 in promoting basal mammary cell epithelial differentiation, at least in part, by regulating FOXO factor function on enhancers to activate TP63 and GRHL3 expression.

Published
2017

39. Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4- and MYC-dependent manner

Author

Mishra, Vivek Kumar, primary, Wegwitz, Florian, additional, Kosinsky, Robyn Laura, additional, Sen, Madhobi, additional, Baumgartner, Roland, additional, Wulff, Tanja, additional, Siveke, Jens T., additional, Schildhaus, Hans-Ulrich, additional, Najafova, Zeynab, additional, Kari, Vijayalakshmi, additional, Kohlhof, Hella, additional, Hessmann, Elisabeth, additional, and Johnsen, Steven A., additional

Published
2017
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40. RNF40 regulates gene expression in an epigenetic context-dependent manner

Author

Xie, Wanhua, primary, Nagarajan, Sankari, additional, Baumgart, Simon J., additional, Kosinsky, Robyn Laura, additional, Najafova, Zeynab, additional, Kari, Vijayalakshmi, additional, Hennion, Magali, additional, Indenbirken, Daniela, additional, Bonn, Stefan, additional, Grundhoff, Adam, additional, Wegwitz, Florian, additional, Mansouri, Ahmed, additional, and Johnsen, Steven A., additional

Published
2017
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41. BRD4 promotes p63 and GRHL3 expression downstream of FOXO in mammary epithelial cells

Author

Nagarajan, Sankari, primary, Bedi, Upasana, additional, Budida, Anusha, additional, Hamdan, Feda H., additional, Mishra, Vivek Kumar, additional, Najafova, Zeynab, additional, Xie, Wanhua, additional, Alawi, Malik, additional, Indenbirken, Daniela, additional, Knapp, Stefan, additional, Chiang, Cheng-Ming, additional, Grundhoff, Adam, additional, Kari, Vijayalakshmi, additional, Scheel, Christina H., additional, Wegwitz, Florian, additional, and Johnsen, Steven A., additional

Published
2016
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42. Abstract 1982: BRD4-FOXO axis maintains differentiated mammary epithelial phenotype by regulating p63 and GRHL3 expression

Author

Nagarajan, Sankari, primary, Bedi, Upasana, additional, Budida, Anusha, additional, Xie, Wanhua, additional, Hamdan, Feda Hisham Moh’d, additional, Mishra, Vivek Kumar, additional, Najafova, Zeynab, additional, Alawi, Malik, additional, Indenbirken, Daniela, additional, Knapp, Stephan, additional, Chiang, Cheng-Ming, additional, Grundhoff, Adam, additional, Scheel, Christina H., additional, Kari, Vijayalakshmi, additional, Wegwitz, Florian, additional, and Johnsen, Steven A., additional

Published
2016
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43. A Subset of Histone H2B Genes Produces Polyadenylated mRNAs under a Variety of Cellular Conditions

Author

Kari, Vijayalakshmi, Karpiuk, Oleksandra, Tieg, Bettina, Kriegs, Malte, Dikomey, Ekkehard, Krebber, Heike, Begus-Nahrmann, Yvonne, Johnsen, Steven A., and Tian, Bin

Subjects
DNA Replication, Cytoplasm, Anatomy and Physiology, Transcription, Genetic, Bone and Mineral Metabolism, Science, Biophysics, Gene Expression, Bone Marrow Cells, Biochemistry, Histones, Molecular cell biology, Histone H2B Genes, mRNAs, Cellular Conditions, Cell Line, Tumor, Genetics, Humans, RNA, Messenger, Bone, Biology, Musculoskeletal System, Osteoblasts, Chromosome Biology, Stem Cells, Mesenchymal Stem Cells, Cell Differentiation, Genomics, Cell Cycle Checkpoints, HCT116 Cells, Chromatin, Up-Regulation, Nucleic acids, Metabolism, RNA processing, Polyribosomes, RNA, Medicine, Epigenetics, Cellular Types, Tumor Suppressor Protein p53, Research Article, Developmental Biology
Abstract

Unlike other metazoan mRNAs, replication-dependent histone gene transcripts are not polyadenylated but instead have a conserved stem-loop structure at their 39 end. Our previous work has shown that under certain conditions replicationdependent histone genes can produce alternative transcripts that are polyadenylated at the 39 end and, in some cases, spliced. A number of microarray studies examining the expression of polyadenylated mRNAs identified changes in the levels of histone transcripts e.g. during differentiation and tumorigenesis. However, it remains unknown which histone genes produce polyadenylated transcripts and which conditions regulate this process. In the present study we examined the expression and polyadenylation of the human histone H2B gene complement in various cell lines. We demonstrate that H2B genes display a distinct expression pattern that is varies between different cell lines. Further we show that the fraction of polyadenylated HIST1H2BD and HIST1H2AC transcripts is increased during differentiation of human mesenchymal stem cells (hMSCs) and human fetal osteoblast (hFOB 1.19). Furthermore, we observed an increased fraction of polyadenylated transcripts produced from the histone genes in cells following ionizing radiation. Finally, we show that polyadenylated transcripts are transported to the cytoplasm and found on polyribosomes. Thus, we propose that the production of polyadenylated histone mRNAs from replication-dependent histone genes is a regulated process induced under specific cellular circumstances. Open-Access-Publikationsfonds 2013 peerReviewed

Published
2013

50. Cytosolic 5'-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites

Author

Patzak, Melanie S, Kari, Vijayalakshmi, Patil, Shilpa, Hamdan, Feda H, Goetze, Robert G, Brunner, Marius, Gaedcke, Jochen, Kitz, Julia, Jodrell, Duncan I, Richards, Frances M, Pilarsky, Christian, Gruetzmann, Robert, Rümmele, Petra, Knösel, Thomas, Hessmann, Elisabeth, Ellenrieder, Volker, Johnsen, Steven A, and Neesse, Albrecht

Subjects
Gene Expression, Mice, Transgenic, Pancreatic cancer, Prognosis, Gemcitabine, Deoxycytidine, Models, Biological, Xenograft Model Antitumor Assays, 3. Good health, Pancreatic Neoplasms, Disease Models, Animal, Mice, Drug Resistance, Neoplasm, Cell Line, Tumor, Biomarkers, Tumor, Animals, Humans, 5'-Nucleotidase, Chemotherapeutic resistance, Cytosolic 5′-nucleotidase 1A, Carcinoma, Pancreatic Ductal
Abstract

BACKGROUND: Cytosolic 5'-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy. METHODS: NT5C1A expression was determined by semiquantitative immunohistochemistry using tissue microarrays. Gemcitabine metabolites and response were assessed in several human and murine PDAC cell lines using crystal violet assays, Western blot, viability assays, and liquid chromatography tandem mass-spectrometry (LC-MS/MS). FINDINGS: NT5C1A was strongly expressed in tumor cells of a large subgroup of resected PDAC patients in two independent patient cohorts (44-56% score 2 and 8-26% score 3, n = 414). In contrast, NT5C1A was expressed at very low levels in the tumor stroma, and neither stromal nor tumoral expression was a prognostic marker for postoperative survival. In vitro, NT5C1A overexpression increased gemcitabine resistance by reducing apoptosis levels and significantly decreased intracellular amounts of cytotoxic dFdCTP in +NT5C1A tumor cells. Co-culture experiments with conditioned media from +NT5C1A PSCs improved gemcitabine efficacy in tumor cells. In vivo, therapeutic efficacy of gemcitabine was significantly decreased and serum levels of the inactive gemcitabine metabolite dFdU significantly increased in mice bearing NT5C1A overexpressing tumors. INTERPRETATION: NT5C1A is robustly expressed in tumor cells of resected PDAC patients. Moreover, NT5C1A mediates gemcitabine resistance by decreasing the amount of intracellular dFdCTP, leading to reduced tumor cell apoptosis and larger pancreatic tumors in mice. Further studies should clarify the role of NT5C1A as novel predictor for gemcitabine treatment response in patients with PDAC.

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