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1. Simultaneous sequencing of genetic and epigenetic bases in DNA

Author

Füllgrabe, Jens, Gosal, Walraj S., Creed, Páidí, Liu, Sidong, Lumby, Casper K., Morley, David J., Ost, Tobias W. B., Vilella, Albert J., Yu, Shirong, Bignell, Helen, Burns, Philippa, Charlesworth, Tom, Fu, Beiyuan, Fordham, Howerd, Harding, Nicolas J., Gandelman, Olga, Golder, Paula, Hodson, Christopher, Li, Mengjie, Lila, Marjana, Liu, Yang, Mason, Joanne, Mellad, Jason, Monahan, Jack M., Nentwich, Oliver, Palmer, Alexandra, Steward, Michael, Taipale, Minna, Vandomme, Audrey, San-Bento, Rita Santo, Singhal, Ankita, Vivian, Julia, Wójtowicz, Natalia, Williams, Nathan, Walker, Nicolas J., Wong, Nicola C. H., Yalloway, Gary N., Holbrook, Joanna D., and Balasubramanian, Shankar

Published
2023
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2. Computational analysis of transcriptional regulation

Author

Monahan, Jack Michael and Enright, Anton James

Subjects
572.8, Cervical carcinogenesis, chromatin interactions, ageing, regulation of transcriptional variability, RNA post-transcriptional modifcations
Abstract

It is doubtful Friedrich Miescher appreciated how groundbreaking and transformative his isolation of ’nuclein’ in 1869 would prove. Eukaryotic gene expression is a noisy process that is subject to multiple layers of regulation. Key features of this are the three-dimensional (3D) chromatin organisation of eukaryotic genomes and the post-transcriptional control of RNA fates. Eukaryotic nuclear DNA is tightly packaged as chromatin that is further folded into higher order structures. The 3D folding of eukaryotic genome lends itself to the formation of interactions between otherwise distant regions of the genome. These interactions modulate transcription. I investigated the impact of human papillomavirus (HPV) 16 integration on host chromatin organisation and transcription using the W12 model for early cervical carcinogenesis with a novel Chromosome Conformation Capture (3C) method that specifically enriches for interactions involving viral integrants. Integration occurs without disrupting host 3D chromatin structure but alters the expression of many neighbouring host genes. The advent of reliable protocols for performing single-cell RNA sequencing (scRNA-seq) has revealed that transcriptional noise is widespread and a biologically important feature in many populations of mammalian cells. Ageing is associated with the progressive decline in biological function. It has recently been described that aged somatic tissues have greater cell-to-cell transcriptional variability. Ageing is also associated with a decline in male fertility. Some have attributed this to the clonal expansion of selfish spermatogonial lineages. To address this, I explored the effect of ageing on the transcriptomes of sorted populations of mouse undifferentiated spermatogonia using bulk and single-cell RNA sequencing (RNAseq). While subtle changes in mean gene expression are detectable, it was apparent that ageing, unlike in somatic tissues, leads to a decline in cell-to-cell transcriptional variability. This may reflect the phenomenon of selfish spermatogonial selection. Finally, I explored the role of an RNA post-transcriptional modification (RPTM), N6- methyladenosine (m6A), in buffering transcriptional noise. Maternally-supplied YTHDF2 is essential for degradation of m6A-modified transcripts during the maternal-to-zygotic transition (MZT) early in mammalian embryogenesis. YTHDF2 targets increase in abundance in its absence. Using scRNA-seq data generated from control and maternal conditional knock-out mouse zygotes I show that many of these targets exhibit greater cell-to-cell transcriptional heterogeneity in the absence of YTHDF2-mediated degradation. Suggesting that YTHDF2 has a additional function in buffering transcriptional noise.

Published
2020
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3. FEHAT: efficient, large scale and automated heartbeat detection in Medaka fish embryos.

Author

Ferreira, Marcio Soares, Stricker, Sebastian, Fitzgerald, Tomas, Monahan, Jack, Defranoux, Fanny, Watson, Philip, Welz, Bettina, Hammouda, Omar, Wittbrodt, Joachim, and Birney, Ewan

Subjects
IMAGE segmentation, FOURIER transforms, HEART beat, CARDIAC imaging, INTEGRATED software
Abstract

Summary High-resolution imaging of model organisms allows the quantification of important physiological measurements. In the case of fish with transparent embryos, these videos can visualize key physiological processes, such as heartbeat. High throughput systems can provide enough measurements for the robust investigation of developmental processes as well as the impact of system perturbations on physiological state. However, few analytical schemes have been designed to handle thousands of high-resolution videos without the need for some level of human intervention. We developed a software package, named FEHAT, to provide a fully automated solution for the analytics of large numbers of heart rate imaging datasets obtained from developing Medaka fish embryos in 96-well plate format imaged on an Acquifer machine. FEHAT uses image segmentation to define regions of the embryo showing changes in pixel intensity over time, followed by the classification of the most likely position of the heart and Fourier Transformations to estimate the heart rate. Here, we describe some important features of the FEHAT software, showcasing its performance across a large set of medaka fish embryos and compare its performance to established, less automated solutions. FEHAT provides reliable heart rate estimates across a range of temperature-based perturbations and can be applied to tens of thousands of embryos without the need for any human intervention. Availability and implementation Data used in this manuscript will be made available on request. [ABSTRACT FROM AUTHOR]

Published
2024
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5. Genomic variations and epigenomic landscape of the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel

Author

Leger, Adrien, Brettell, Ian, Monahan, Jack, Barton, Carl, Wolf, Nadeshda, Kusminski, Natalja, Herder, Cathrin, Aadepu, Narendar, Becker, Clara, Gierten, Jakob, Hammouda, Omar T., Hasel, Eva, Lischik, Colin, Lust, Katharina, Sokolova, Natalia, Suzuki, Risa, Tavhelidse, Tinatini, Thumberger, Thomas, Tsingos, Erika, Watson, Philip, Welz, Bettina, Naruse, Kiyoshi, Loosli, Felix, Wittbrodt, Joachim, Birney, Ewan, and Fitzgerald, Tomas

Published
2022
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6. The Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel

Author

Fitzgerald, Tomas, Brettell, Ian, Leger, Adrien, Wolf, Nadeshda, Kusminski, Natalja, Monahan, Jack, Barton, Carl, Herder, Cathrin, Aadepu, Narendar, Gierten, Jakob, Becker, Clara, Hammouda, Omar T., Hasel, Eva, Lischik, Colin, Lust, Katharina, Sokolova, Natalia, Suzuki, Risa, Tsingos, Erika, Tavhelidse, Tinatini, Thumberger, Thomas, Watson, Philip, Welz, Bettina, Khouja, Nadia, Naruse, Kiyoshi, Birney, Ewan, Wittbrodt, Joachim, and Loosli, Felix

Published
2022
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7. IL10RA modulates crizotinib sensitivity in NPM1-ALK+ anaplastic large cell lymphoma

Author

Prokoph, Nina, Probst, Nicola A., Lee, Liam C., Monahan, Jack M., Matthews, Jamie D., Liang, Huan-Chang, Bahnsen, Klaas, Montes-Mojarro, Ivonne A., Karaca-Atabay, Elif, Sharma, Geeta G., Malik, Vikas, Larose, Hugo, Forde, Sorcha D., Ducray, Stephen P., Lobello, Cosimo, Wang, Qi, Luan, Shi-Lu, Pospíšilová, Šárka, Gambacorti-Passerini, Carlo, Burke, G. A. Amos, Pervez, Shahid, Attarbaschi, Andishe, Janíková, Andrea, Pacquement, Hélène, Landman-Parker, Judith, Lambilliotte, Anne, Schleiermacher, Gudrun, Klapper, Wolfram, Jauch, Ralf, Woessmann, Wilhelm, Vassal, Gilles, Kenner, Lukas, Merkel, Olaf, Mologni, Luca, Chiarle, Roberto, Brugières, Laurence, Geoerger, Birgit, Barbieri, Isaia, and Turner, Suzanne D.

Published
2020
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11. Accurate simultaneous sequencing of genetic and epigenetic bases in DNA

Author

Füllgrabe, Jens, primary, Gosal, Walraj S, additional, Creed, Páidí, additional, Liu, Sidong, additional, Lumby, Casper K, additional, Morley, David J, additional, Ost, Tobias W B, additional, Vilella, Albert J, additional, Yu, Shirong, additional, Bignell, Helen, additional, Burns, Philippa, additional, Charlesworth, Tom, additional, Fu, Beiyuan, additional, Fordham, Howerd, additional, Harding, Nick, additional, Gandelman, Olga, additional, Golder, Paula, additional, Hodson, Christopher, additional, Li, Mengjie, additional, Lila, Marjana, additional, Liu, Yang, additional, Mason, Joanne, additional, Mellad, Jason, additional, Monahan, Jack, additional, Nentwich, Oliver, additional, Palmer, Alexandra, additional, Steward, Michael, additional, Taipale, Minna, additional, Vandomme, Audrey, additional, San-Bento, Rita Santo, additional, Singhal, Ankita, additional, Vivian, Julia, additional, Wójtowicz, Natalia, additional, Williams, Nathan, additional, Walker, Nicolas J, additional, Wong, Nicola C H, additional, Yalloway, Gary, additional, Holbrook, Joanna D, additional, and Balasubaramanian, Shankar, additional

Published
2022
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13. Additional file 10 of Genomic variations and epigenomic landscape of the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel

Author

Leger, Adrien, Brettell, Ian, Monahan, Jack, Barton, Carl, Wolf, Nadeshda, Kusminski, Natalja, Herder, Cathrin, Aadepu, Narendar, Becker, Clara, Gierten, Jakob, Hammouda, Omar T., Hasel, Eva, Lischik, Colin, Lust, Katharina, Sokolova, Natalia, Suzuki, Risa, Tavhelidse, Tinatini, Thumberger, Thomas, Tsingos, Erika, Watson, Philip, Welz, Bettina, Naruse, Kiyoshi, Loosli, Felix, Wittbrodt, Joachim, Birney, Ewan, and Fitzgerald, Tomas

Abstract

Additional file 10. Review history.

Published
2022
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14. Additional file 8 of Genomic variations and epigenomic landscape of the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel

Author

Leger, Adrien, Brettell, Ian, Monahan, Jack, Barton, Carl, Wolf, Nadeshda, Kusminski, Natalja, Herder, Cathrin, Aadepu, Narendar, Becker, Clara, Gierten, Jakob, Hammouda, Omar T., Hasel, Eva, Lischik, Colin, Lust, Katharina, Sokolova, Natalia, Suzuki, Risa, Tavhelidse, Tinatini, Thumberger, Thomas, Tsingos, Erika, Watson, Philip, Welz, Bettina, Naruse, Kiyoshi, Loosli, Felix, Wittbrodt, Joachim, Birney, Ewan, and Fitzgerald, Tomas

Abstract

Additional file 8: Figure S6. Circos plots. Circos plots for structural variants (DEL, INS, DUP, INV, TRA) discovered by the reference-anchored approach.

Published
2022
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15. Additional file 10 of The Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel

Author

Fitzgerald, Tomas, Brettell, Ian, Leger, Adrien, Wolf, Nadeshda, Kusminski, Natalja, Monahan, Jack, Barton, Carl, Herder, Cathrin, Aadepu, Narendar, Gierten, Jakob, Becker, Clara, Hammouda, Omar T., Hasel, Eva, Lischik, Colin, Lust, Katharina, Sokolova, Natalia, Suzuki, Risa, Tsingos, Erika, Tavhelidse, Tinatini, Thumberger, Thomas, Watson, Philip, Welz, Bettina, Khouja, Nadia, Naruse, Kiyoshi, Birney, Ewan, Wittbrodt, Joachim, and Loosli, Felix

Abstract

Additional file 10. Review history.

Published
2022
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16. Additional file 8 of The Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel

Author

Fitzgerald, Tomas, Brettell, Ian, Leger, Adrien, Wolf, Nadeshda, Kusminski, Natalja, Monahan, Jack, Barton, Carl, Herder, Cathrin, Aadepu, Narendar, Gierten, Jakob, Becker, Clara, Hammouda, Omar T., Hasel, Eva, Lischik, Colin, Lust, Katharina, Sokolova, Natalia, Suzuki, Risa, Tsingos, Erika, Tavhelidse, Tinatini, Thumberger, Thomas, Watson, Philip, Welz, Bettina, Khouja, Nadia, Naruse, Kiyoshi, Birney, Ewan, Wittbrodt, Joachim, and Loosli, Felix

Subjects
mental disorders, population characteristics, human activities, geographic locations, humanities
Abstract

Additional file 8: Figure S9. Copenhagen plot. Plot showing genomic positions of significant eQTL SNPs.

Published
2022
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17. Additional file 2 of Genomic variations and epigenomic landscape of the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel

Author

Leger, Adrien, Brettell, Ian, Monahan, Jack, Barton, Carl, Wolf, Nadeshda, Kusminski, Natalja, Herder, Cathrin, Aadepu, Narendar, Becker, Clara, Gierten, Jakob, Hammouda, Omar T., Hasel, Eva, Lischik, Colin, Lust, Katharina, Sokolova, Natalia, Suzuki, Risa, Tavhelidse, Tinatini, Thumberger, Thomas, Tsingos, Erika, Watson, Philip, Welz, Bettina, Naruse, Kiyoshi, Loosli, Felix, Wittbrodt, Joachim, Birney, Ewan, and Fitzgerald, Tomas

Abstract

Additional file 2: Figures S1-S5. Supplementary figures. Various supplementary figures.

Published
2022
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18. Additional file 4 of The Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel

Author

Fitzgerald, Tomas, Brettell, Ian, Leger, Adrien, Wolf, Nadeshda, Kusminski, Natalja, Monahan, Jack, Barton, Carl, Herder, Cathrin, Aadepu, Narendar, Gierten, Jakob, Becker, Clara, Hammouda, Omar T., Hasel, Eva, Lischik, Colin, Lust, Katharina, Sokolova, Natalia, Suzuki, Risa, Tsingos, Erika, Tavhelidse, Tinatini, Thumberger, Thomas, Watson, Philip, Welz, Bettina, Khouja, Nadia, Naruse, Kiyoshi, Birney, Ewan, Wittbrodt, Joachim, and Loosli, Felix

Abstract

Additional file 4: Figures S1-S8. Supplementary figures. Various supplementary figures.

Published
2022
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19. Additional file 9 of The Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel

Author

Fitzgerald, Tomas, Brettell, Ian, Leger, Adrien, Wolf, Nadeshda, Kusminski, Natalja, Monahan, Jack, Barton, Carl, Herder, Cathrin, Aadepu, Narendar, Gierten, Jakob, Becker, Clara, Hammouda, Omar T., Hasel, Eva, Lischik, Colin, Lust, Katharina, Sokolova, Natalia, Suzuki, Risa, Tsingos, Erika, Tavhelidse, Tinatini, Thumberger, Thomas, Watson, Philip, Welz, Bettina, Khouja, Nadia, Naruse, Kiyoshi, Birney, Ewan, Wittbrodt, Joachim, and Loosli, Felix

Abstract

Additional file 9: Figure S10. Haploview plots. Linkage disequilibrium (LD) plots generated with Haploview for each of the 24 medaka chromosomes, showing r2 values in the MIKK panel for each pair of SNPs within 1 Mb of one another.

Published
2022
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20. BRG1 and NPM-ALK Are Co-Regulated in Anaplastic Large-Cell Lymphoma; BRG1 Is a Potential Therapeutic Target in ALCL

Author

Garland, Gavin D., primary, Ducray, Stephen P., additional, Jahangiri, Leila, additional, Pucci, Perla, additional, Amos Burke, G. A., additional, Monahan, Jack, additional, Lai, Raymond, additional, Merkel, Olaf, additional, Schiefer, Ana-Iris, additional, Kenner, Lukas, additional, Bannister, Andrew J., additional, and Turner, Suzanne D., additional

Published
2021
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21. Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis

Author

Groves, Ian J., primary, Drane, Emma L. A., additional, Michalski, Marco, additional, Monahan, Jack M., additional, Scarpini, Cinzia G., additional, Smith, Stephen P., additional, Bussotti, Giovanni, additional, Várnai, Csilla, additional, Schoenfelder, Stefan, additional, Fraser, Peter, additional, Enright, Anton J., additional, and Coleman, Nicholas, additional

Published
2021
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22. The Medaka Inbred Kiyosu-Karlsruhe (MIKK) Panel

Author

Fitzgerald, Tomas, primary, Brettell, Ian, additional, Leger, Adrien, additional, Wolf, Nadeshda, additional, Kusminski, Natalja, additional, Monahan, Jack, additional, Barton, Carl, additional, Herder, Cathrin, additional, Aadepu, Narendar, additional, Gierten, Jakob, additional, Becker, Clara, additional, Hammouda, Omar T., additional, Hasel, Eva, additional, Lischik, Colin, additional, Lust, Katharina, additional, Suzuki, Risa, additional, Tsingos, Erika, additional, Tavhelidse, Tinatini, additional, Thumberger, Thomas, additional, Watson, Philip, additional, Welz, Bettina, additional, Khouja, Nadia, additional, Naruse, Kiyoshi, additional, Birney, Ewan, additional, Wittbrodt, Joachim, additional, and Loosli, Felix, additional

Published
2021
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23. Genomic variations and epigenomic landscape of the Medaka Inbred Kiyosu-Karlsruhe (MIKK) panel

Author

Leger, Adrien, primary, Brettell, Ian, additional, Monahan, Jack, additional, Barton, Carl, additional, Wolf, Nadeshda, additional, Kusminski, Natalja, additional, Herder, Cathrin, additional, Aadepu, Narendar, additional, Becker, Clara, additional, Gierten, Jakob, additional, Hammouda, Omar T., additional, Hasel, Eva, additional, Lischik, Colin, additional, Lust, Katharina, additional, Suzuki, Risa, additional, Tavhelidse, Tinatini, additional, Thumberger, Thomas, additional, Tsingos, Erika, additional, Watson, Philip, additional, Welz, Bettina, additional, Naruse, Kiyoshi, additional, Loosli, Felix, additional, Wittbrodt, Joachim, additional, Birney, Ewan, additional, and Fitzgerald, Tomas, additional

Published
2021
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24. Three-dimensional interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis

Author

Groves, Ian J, primary, Drane, Emma LA, additional, Michalski, Marco, additional, Monahan, Jack M, additional, Scarpini, Cinzia G, additional, Smith, Stephen P, additional, Bussotti, Giovanni, additional, Várnai, Csilla, additional, Schoenfelder, Stefan, additional, Fraser, Peter, additional, Enright, Anton J, additional, and Coleman, Nicholas, additional

Published
2021
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25. IL10RA Modulates Crizotinib Sensitivity in NPM1-ALK-positive Anaplastic Large Cell Lymphoma

Author

Prokoph, Nina, primary, Probst, Nicola Anna, primary, Lee, Liam Changwoo, primary, Monahan, Jack Michael, primary, Matthews, Jamie David, primary, Liang, Huan-Chang, primary, Bahnsen, Klaas, primary, Montes-Mojarro, Ivonne A, primary, Karaca Atabay, Elif, primary, Sharma, Geeta Geeta, primary, Malik, Vikas, primary, Larose, Hugo, primary, Forde, Sorcha Denise, primary, Ducray, Stephen Paul, primary, Lobello, Cosimo, primary, Wang, Qi, primary, Luan, Shi-Lu, primary, Pospisilova, Sarka, primary, Gambacorti-Passerini, Carlo B, primary, Burke, Amos, primary, Pervez, Shahid, primary, Attarbaschi, Andishe, primary, Janikova, Andrea, primary, Pacquement, Helene, primary, Landman-Parker, Judith, primary, Lambilliotte, Anne, primary, Schleiermacher, Gudrun, primary, Klapper, Wolfram, primary, Jauch, Ralf, primary, Woessmann, Wilhelm, primary, Vassal, Gilles, primary, Kenner, Lukas, primary, Merkel, Olaf, primary, Mologni, Luca, primary, Chiarle, Roberto, primary, Brugieres, Laurence, primary, Geoerger, Birgit, primary, Barbieri, Isaia, primary, and Turner, Suzanne D, primary

Published
2020
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27. The RNA m6A Reader YTHDF2 Is Essential for the Post-transcriptional Regulation of the Maternal Transcriptome and Oocyte Competence

Author

Ivanova, Ivayla, Much, Christian, Di Giacomo, Monica, Azzi, Chiara, Morgan, Marcos, Ventura De Oliveira Moreira, Pedro, Monahan, Jack, Carrieri, Claudia, Enright, Anton J, O'Carroll, Donal, Enright, Anton [0000-0002-6090-3100], and Apollo - University of Cambridge Repository

Subjects
Mice, Knockout, Binding Sites, Genotype, Transcription, Genetic, Zygote, maternal transcriptome, Gene Expression Regulation, Developmental, RNA-Binding Proteins, m(6)A-reader, m(6)A, Mice, Inbred C57BL, Meiosis, oocyte maturation, Fertility, Phenotype, YTHDF2, Oocytes, Animals, Female, RNA, Messenger, RNA Processing, Post-Transcriptional, Transcriptome, Infertility, Female, Protein Binding
Abstract

YTHDF2 binds and destabilizes N6-methyladenosine (m6A)-modified mRNA. The extent to which this branch of m6A RNA-regulatory pathway functions in vivo and contributes to mammalian development remains unknown. Here we find that YTHDF2 deficiency is partially permissive in mice and results in female-specific infertility. Using conditional mutagenesis, we demonstrate that YTHDF2 is autonomously required within the germline to produce MII oocytes that are competent to sustain early zygotic development. Oocyte maturation is associated with a wave of maternal RNA degradation, and the resulting relative changes to the MII transcriptome are integral to oocyte quality. The loss of YTHDF2 results in the failure to regulate transcript dosage of a cohort of genes during oocyte maturation, with enrichment observed for the YTHDF2-binding consensus and evidence of m6A in these upregulated genes. In summary, the m6A-reader YTHDF2 is an intrinsic determinant of mammalian oocyte competence and early zygotic development.

Published
2018
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30. IL10RA modulates crizotinib sensitivity in NPM1-ALK+anaplastic large cell lymphoma

Author

Prokoph, Nina, Probst, Nicola A., Lee, Liam C., Monahan, Jack M., Matthews, Jamie D., Liang, Huan-Chang, Bahnsen, Klaas, Montes-Mojarro, Ivonne A., Karaca-Atabay, Elif, Sharma, Geeta G., Malik, Vikas, Larose, Hugo, Forde, Sorcha D., Ducray, Stephen P., Lobello, Cosimo, Wang, Qi, Luan, Shi-Lu, Pospíšilová, Šárka, Gambacorti-Passerini, Carlo, Burke, G. A. Amos, Pervez, Shahid, Attarbaschi, Andishe, Janíková, Andrea, Pacquement, Hélène, Landman-Parker, Judith, Lambilliotte, Anne, Schleiermacher, Gudrun, Klapper, Wolfram, Jauch, Ralf, Woessmann, Wilhelm, Vassal, Gilles, Kenner, Lukas, Merkel, Olaf, Mologni, Luca, Chiarle, Roberto, Brugières, Laurence, Geoerger, Birgit, Barbieri, Isaia, and Turner, Suzanne D.

Abstract

Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor–relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance–specific relapse.

Published
2020
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33. BRG1 and NPM-ALK Are Co-Regulated in Anaplastic Large-Cell Lymphoma; BRG1 Is a Potential Therapeutic Target in ALCL.

Author

Garland, Gavin D., Ducray, Stephen P., Jahangiri, Leila, Pucci, Perla, Amos Burke, G. A., Monahan, Jack, Lai, Raymond, Merkel, Olaf, Schiefer, Ana-Iris, Kenner, Lukas, Bannister, Andrew J., and Turner, Suzanne D.

Subjects
DISEASE progression, GENE expression, CELLULAR signal transduction, CELL cycle, CELL lines, TRANSCRIPTION factors, T-cell lymphoma
Abstract

Simple Summary: T-cell lymphoma is a cancer of the immune system. One specific sub-type of T-cell lymphoma is a malignancy called anaplastic large cell lymphoma (ALCL), which is distinct from the other forms, as in general, it has a better prognosis. Research conducted to understand why ALCL develops has shown that a specific genetic event occurs, whereby a new protein is created that drives tumour growth. This protein is called nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). Our research, described here, shows that NPM-ALK regulates another protein, called BRG1, to drive proliferation of tumour cells. In turn, when the gene that leads to expression of BRG1 is inactivated, the tumour cells die. These data suggest that therapeutic targeting of BRG1 might be a novel therapy for this form of cancer. Anaplastic large-cell lymphoma (ALCL) is a T-cell malignancy driven in many cases by the product of a chromosomal translocation, nucleophosmin–anaplastic lymphoma kinase (NPM-ALK). NPM-ALK activates a plethora of pathways that drive the hallmarks of cancer, largely signalling pathways normally associated with cytokine and/or T-cell receptor-induced signalling. However, NPM-ALK is also located in the nucleus and its functions in this cellular compartment for the most part remain to be determined. We show that ALCL cell lines and primary patient tumours express the transcriptional activator BRG1 in a NPM-ALK-dependent manner. NPM-ALK regulates expression of BRG1 by post-translational mechanisms dependent on its kinase activity, protecting it from proteasomal degradation. Furthermore, we show that BRG1 drives a transcriptional programme associated with cell cycle progression. In turn, inhibition of BRG1 expression with specific shRNA decreases cell viability, suggesting that it may represent a key therapeutic target for the treatment of ALCL. [ABSTRACT FROM AUTHOR]

Published
2022
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34. LETTERS TO THE EDITOR.

Author

FARIA, CHUCK, MONAHAN, JACK, MOE, TOM, BOWEN, JIM, SCHRIVER, COLLIN, BUSBEY, CHARLES, JETER, KERRI, MANNI, KENNY, JORDAN, EDWARD, and PETERSON, JEANNIE

Subjects
WOMEN veterans
Published
2021

35. Automating front-end multi-peril policy writing

Author

Monahan, Jack

Subjects
Allstate Insurance Co. -- Information management, Property and casualty insurance -- Information management, Insurance industry -- Information management, Electronic data processing -- Usage, Business, Insurance
Published
1983

36. VET VOICE.

Author

Gardner, Gary, Thacker, Jim, Kearney, William R., Weaver, Jim, Cogliati, Robert, Monahan, Jack, and Amme, Richard C.

Subjects
WEBSITES, VETERANS
Abstract

Several letters to the editor are presented including one on USAJOBS website, one on exposure of veterans to radiation, and one in response to an article on the Mexican punitive expedition in the March 2016 issue.

Published
2016

37. Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis

Author

Stephen Smith, Giovanni Bussotti, Cinzia G. Scarpini, Nicholas Coleman, Peter Fraser, Stefan Schoenfelder, Jack M. Monahan, Anton J. Enright, Ian J. Groves, Csilla Várnai, Emma L. A. Drane, Marco Michalski, Groves, Ian J [0000-0001-8882-6701], Michalski, Marco [0000-0002-8470-2338], Monahan, Jack M [0000-0002-0635-0015], Scarpini, Cinzia G [0000-0003-4730-5197], Smith, Stephen P [0000-0001-7744-3238], Várnai, Csilla [0000-0003-0048-9507], Fraser, Peter [0000-0002-0041-1227], Enright, Anton J [0000-0002-6090-3100], Apollo - University of Cambridge Repository, Groves, Ian J. [0000-0001-8882-6701], Monahan, Jack M. [0000-0002-0635-0015], Scarpini, Cinzia G. [0000-0003-4730-5197], Smith, Stephen P. [0000-0001-7744-3238], and Enright, Anton J. [0000-0002-6090-3100]

Subjects
Carcinogenesis, Clone (cell biology), DNA cloning, Gene Expression, Uterine Cervical Neoplasms, Pathology and Laboratory Medicine, Genome, Epigenesis, Genetic, Gene expression, Medicine and Health Sciences, Tumor Cells, Cultured, Biology (General), Genetics, Viral Genomics, Human papillomavirus 16, Genomics, Chromatin, Medical Microbiology, Viral Pathogens, Viruses, Female, Gene Cloning, Pathogens, Research Article, Papillomaviruses, QH301-705.5, Virus Integration, Immunology, Microbial Genomics, Genome, Viral, Biology, Molecular cloning, Research and Analysis Methods, Microbiology, HPV-16, Virus Effects on Host Gene Expression, Virology, Humans, Epigenetics, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, Gene, Biology and life sciences, Papillomavirus Infections, Organisms, RC581-607, Parasitology, Immunologic diseases. Allergy, DNA viruses, Cloning
Abstract

Development of cervical cancer is directly associated with integration of human papillomavirus (HPV) genomes into host chromosomes and subsequent modulation of HPV oncogene expression, which correlates with multi-layered epigenetic changes at the integrated HPV genomes. However, the process of integration itself and dysregulation of host gene expression at sites of integration in our model of HPV16 integrant clone natural selection has remained enigmatic. We now show, using a state-of-the-art ‘HPV integrated site capture’ (HISC) technique, that integration likely occurs through microhomology-mediated repair (MHMR) mechanisms via either a direct process, resulting in host sequence deletion (in our case, partially homozygously) or via a ‘looping’ mechanism by which flanking host regions become amplified. Furthermore, using our ‘HPV16-specific Region Capture Hi-C’ technique, we have determined that chromatin interactions between the integrated virus genome and host chromosomes, both at short- (500 kbp), appear to drive local host gene dysregulation through the disruption of host:host interactions within (but not exceeding) host structures known as topologically associating domains (TADs). This mechanism of HPV-induced host gene expression modulation indicates that integration of virus genomes near to or within a ‘cancer-causing gene’ is not essential to influence their expression and that these modifications to genome interactions could have a major role in selection of HPV integrants at the early stage of cervical neoplastic progression., Author summary The integration of human papillomaviruses (HPVs) into host chromosomes is a major feature of HPV-associated cancers, however the process by which this occurs and subsequently drives carcinogenesis is incompletely understood. Here, we devised a state-of-the-art HPV16 genome-specific DNA capture technology to precisely determine the host integration sites at a nucleotide resolution, such that we confirm the mechanism of microhomology-mediated repair (MHMR) during both ‘direct’ and ‘looping’ integration of HPV16 genomes into the host. Furthermore, our technology detects both short- and long-range interactions between HPV16 and host chromatin after virus integration, which correlates with dysregulation of host gene expression at distances up to 500kbp from the integration site. This means that HPV16 genomes can directly affect host gene expression much further away on host chromosomes than initially thought, which may lead to competitive growth advantages for certain integrated clones. Therefore, our study provides further insight into the mechanisms by which papillomaviruses are able to initiate and drive cervical carcinogenesis at an early stage after HPV integration.

Published
2021

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