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2. A resource of targeted mutant mouse lines for 5,061 genes

Author

Birling, Marie-Christine, Yoshiki, Atsushi, Adams, David J, Ayabe, Shinya, Beaudet, Arthur L, Bottomley, Joanna, Bradley, Allan, Brown, Steve DM, Bürger, Antje, Bushell, Wendy, Chiani, Francesco, Chin, Hsian-Jean Genie, Christou, Skevoulla, Codner, Gemma F, DeMayo, Francesco J, Dickinson, Mary E, Doe, Brendan, Donahue, Leah Rae, Fray, Martin D, Gambadoro, Alessia, Gao, Xiang, Gertsenstein, Marina, Gomez-Segura, Alba, Goodwin, Leslie O, Heaney, Jason D, Hérault, Yann, de Angelis, Martin Hrabe, Jiang, Si-Tse, Justice, Monica J, Kasparek, Petr, King, Ruairidh E, Kühn, Ralf, Lee, Ho, Lee, Young Jae, Liu, Zhiwei, Lloyd, KC Kent, Lorenzo, Isabel, Mallon, Ann-Marie, McKerlie, Colin, Meehan, Terrence F, Fuentes, Violeta Munoz, Newman, Stuart, Nutter, Lauryl MJ, Oh, Goo Taeg, Pavlovic, Guillaume, Ramirez-Solis, Ramiro, Rosen, Barry, Ryder, Edward J, Santos, Luis A, Schick, Joel, Seavitt, John R, Sedlacek, Radislav, Seisenberger, Claudia, Seong, Je Kyung, Skarnes, William C, Sorg, Tania, Steel, Karen P, Tamura, Masaru, Tocchini-Valentini, Glauco P, Wang, Chi-Kuang Leo, Wardle-Jones, Hannah, Wattenhofer-Donzé, Marie, Wells, Sara, Wiles, Michael V, Willis, Brandon J, Wood, Joshua A, Wurst, Wolfgang, Xu, Ying, Teboul, Lydia, and Murray, Stephen A

Subjects
Biological Sciences, Genetics, Animals, Gene Deletion, Genetic Association Studies, Genome, Genotype, Information Dissemination, International Cooperation, Internet, Mice, Mice, Knockout, Mouse Embryonic Stem Cells, Mutagenesis, Phenotype, International Mouse Phenotyping Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

The International Mouse Phenotyping Consortium reports the generation of new mouse mutant strains for over 5,000 genes, including 2,850 novel null, 2,987 novel conditional- ready, and 4,433 novel reporter alleles.

Published
2021

5. A guideline on the molecular ecosystem regulating ferroptosis

Author

Dai, Enyong, Chen, Xin, Linkermann, Andreas, Jiang, Xuejun, Kang, Rui, Kagan, Valerian E., Bayir, Hülya, Yang, Wan Seok, Garcia-Saez, Ana J., Ioannou, Maria S., Janowitz, Tobias, Ran, Qitao, Gu, Wei, Gan, Boyi, Krysko, Dmitri V., Zhu, Xiaofeng, Wang, Jiayi, Krautwald, Stefan, Toyokuni, Shinya, Xie, Yangchun, Greten, Florian R., Yi, Qing, Schick, Joel, Liu, Jiao, Gabrilovich, Dmitry I., Liu, Jinbao, Zeh, Herbert J., Zhang, Donna D., Yang, Minghua, Iovanna, Juan, Kopf, Manfred, Adolph, Timon E., Chi, Jen-Tsan, Li, Changfeng, Ichijo, Hidenori, Karin, Michael, Sankaran, Vijay G., Zou, Weiping, Galluzzi, Lorenzo, Bush, Ashley I., Li, Binghui, Melino, Gerry, Baehrecke, Eric H., Lotze, Michael T., Klionsky, Daniel J., Stockwell, Brent R., Kroemer, Guido, and Tang, Daolin

Abstract

Ferroptosis, an intricately regulated form of cell death characterized by uncontrolled lipid peroxidation, has garnered substantial interest since this term was first coined in 2012. Recent years have witnessed remarkable progress in elucidating the detailed molecular mechanisms that govern ferroptosis induction and defence, with particular emphasis on the roles of heterogeneity and plasticity. In this Review, we discuss the molecular ecosystem of ferroptosis, with implications that may inform and enable safe and effective therapeutic strategies across a broad spectrum of diseases.

Published
2024
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6. The mammalian gene function resource: the International Knockout Mouse Consortium.

Author

Bradley, Allan, Anastassiadis, Konstantinos, Ayadi, Abdelkader, Battey, James F, Bell, Cindy, Birling, Marie-Christine, Bottomley, Joanna, Brown, Steve D, Bürger, Antje, Bult, Carol J, Bushell, Wendy, Collins, Francis S, Desaintes, Christian, Doe, Brendan, Economides, Aris, Eppig, Janan T, Finnell, Richard H, Fletcher, Colin, Fray, Martin, Frendewey, David, Friedel, Roland H, Grosveld, Frank G, Hansen, Jens, Hérault, Yann, Hicks, Geoffrey, Hörlein, Andreas, Houghton, Richard, Hrabé de Angelis, Martin, Huylebroeck, Danny, Iyer, Vivek, de Jong, Pieter J, Kadin, James A, Kaloff, Cornelia, Kennedy, Karen, Koutsourakis, Manousos, Lloyd, KC Kent, Marschall, Susan, Mason, Jeremy, McKerlie, Colin, McLeod, Michael P, von Melchner, Harald, Moore, Mark, Mujica, Alejandro O, Nagy, Andras, Nefedov, Mikhail, Nutter, Lauryl M, Pavlovic, Guillaume, Peterson, Jane L, Pollock, Jonathan, Ramirez-Solis, Ramiro, Rancourt, Derrick E, Raspa, Marcello, Remacle, Jacques E, Ringwald, Martin, Rosen, Barry, Rosenthal, Nadia, Rossant, Janet, Ruiz Noppinger, Patricia, Ryder, Ed, Schick, Joel Zupicich, Schnütgen, Frank, Schofield, Paul, Seisenberger, Claudia, Selloum, Mohammed, Simpson, Elizabeth M, Skarnes, William C, Smedley, Damian, Stanford, William L, Stewart, A Francis, Stone, Kevin, Swan, Kate, Tadepally, Hamsa, Teboul, Lydia, Tocchini-Valentini, Glauco P, Valenzuela, David, West, Anthony P, Yamamura, Ken-ichi, Yoshinaga, Yuko, and Wurst, Wolfgang

Subjects
Animals, Mice, Knockout, Mice, Internationality, Internet, Knockout, Genetics, Genetics & Heredity
Abstract

In 2007, the International Knockout Mouse Consortium (IKMC) made the ambitious promise to generate mutations in virtually every protein-coding gene of the mouse genome in a concerted worldwide action. Now, 5 years later, the IKMC members have developed high-throughput gene trapping and, in particular, gene-targeting pipelines and generated more than 17,400 mutant murine embryonic stem (ES) cell clones and more than 1,700 mutant mouse strains, most of them conditional. A common IKMC web portal (www.knockoutmouse.org) has been established, allowing easy access to this unparalleled biological resource. The IKMC materials considerably enhance functional gene annotation of the mammalian genome and will have a major impact on future biomedical research.

Published
2012

9. Molecular Signature of Astrocytes for Gene Delivery by the Synthetic Adeno‐Associated Viral Vector rAAV9P1

Author

Bauer, Amelie, primary, Puglisi, Matteo, additional, Nagl, Dennis, additional, Schick, Joel A, additional, Werner, Thomas, additional, Klingl, Andreas, additional, El Andari, Jihad, additional, Hornung, Veit, additional, Kessler, Horst, additional, Götz, Magdalena, additional, Grimm, Dirk, additional, and Brack‐Werner, Ruth, additional

Published
2022
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15. Cannabidiol converts NF-κB into a tumor suppressor in glioblastoma with defined antioxidative properties

Author

Volmar, Marie N M, primary, Cheng, Jiying, additional, Alenezi, Haitham, additional, Richter, Sven, additional, Haug, Alisha, additional, Hassan, Zonera, additional, Goldberg, Maria, additional, Li, Yuping, additional, Hou, Mengzhuo, additional, Herold-Mende, Christel, additional, Maire, Cecile L, additional, Lamszus, Katrin, additional, Flüh, Charlotte, additional, Held-Feindt, Janka, additional, Gargiulo, Gaetano, additional, Topping, Geoffrey J, additional, Schilling, Franz, additional, Saur, Dieter, additional, Schneider, Günter, additional, Synowitz, Michael, additional, Schick, Joel A, additional, Kälin, Roland E, additional, and Glass, Rainer, additional

Published
2021
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16. Human and mouse essentiality screens as a resource for disease gene discovery

Author

Cacheiro, Pilar, Muñoz-Fuentes, Violeta, Westerberg, Henrik, Scott, R. H., Siddiq, A., Sieghart, A., Smith, K. R., Sosinsky, A., Spooner, W., Stevens, H. E., Stuckey, A., Sultana, R., Thomas, E. R. A., Konopka, Tomasz, Thompson, S. R., Tregidgo, C., Tucci, A., Walsh, E., Watters, S. A., Welland, M. J., Williams, E., Witkowska, K., Wood, S. M., Zarowiecki, M., Hsu, Chih-Wei, Marschall, Susan, Lengger, Christoph, Maier, Holger, Seisenberger, Claudia, Bürger, Antje, Kühn, Ralf, Schick, Joel, Hörlein, Andreas, Oritz, Oskar, Giesert, Florian, Christiansen, Audrey, Beig, Joachim, Kenyon, Janet, Codner, Gemma, Fray, Martin, Johnson, Sara J, Cleak, James, Szoke-Kovacs, Zsombor, Lafont, David, Vancollie, Valerie E, McLaren, Robbie S B, Lanza, Denise G, Hughes-Hallett, Lena, Rowley, Christine, Sanderson, Emma, Galli, Antonella, Tuck, Elizabeth, Green, Angela, Tudor, Catherine, Siragher, Emma, Dabrowska, Monika, Mazzeo, Cecilia Icoresi, Beaudet, Arthur L, Griffiths, Mark, Gannon, David, Doe, Brendan, Cockle, Nicola, Kirton, Andrea, Bottomley, Joanna, Ingle, Catherine, Ryder, Edward, Gleeson, Diane, Ramirez-Solis, Ramiro, Heaney, Jason D, Birling, Marie-Christine, Pavlovic, Guillaume, Ayadi, Abdel, Hamid, Meziane, About, Ghina Bou, Champy, Marie-France, Jacobs, Hugues, Wendling, Olivia, Leblanc, Sophie, Vasseur, Laurent, Fuchs, Helmut, Chesler, Elissa J, Kumar, Vivek, White, Jacqueline K, Svenson, Karen L, Wiegand, Jean-Paul, Anderson, Laura L, Wilcox, Troy, Clark, James, Ryan, Jennifer, Denegre, James, Gailus-Durner, Valerie, Stearns, Tim, Philip, Vivek, Witmeyer, Catherine, Bates, Lindsay, Seavey, Zachary, Stanley, Pamela, Willet, Amelia, Roper, Willson, Creed, Julie, Moore, Michayla, Sorg, Tania, Dorr, Alex, Fraungruber, Pamelia, Presby, Rose, Mckay, Matthew, Nguyen-Bresinsky, Dong, Goodwin, Leslie, Urban, Rachel, Kane, Coleen, Murray, Stephen A, Prochazka, Jan, Novosadova, Vendula, Lelliott, Christopher J, Wardle-Jones, Hannah, Wells, Sara, Teboul, Lydia, Cater, Heather, Stewart, Michelle, Hough, Tertius, Wurst, Wolfgang, Dickinson, Mary E, Sedlacek, Radislav, Adams, David J, Seavitt, John R, Tocchini-Valentini, Glauco, Mammano, Fabio, Braun, Robert E, McKerlie, Colin, Herault, Yann, de Angelis, Martin Hrabě, Mallon, Ann-Marie, Bucan, Maja, Lloyd, K C Kent, Brown, Steve D M, Parkinson, Helen, Meehan, Terrence F, Smedley, Damian, Consortium, Genomics England Research, Consortium, International Mouse Phenotyping, Ambrose, J. C., Arumugam, P., Baple, E. L., Nutter, Lauryl M J, Bleda, M., Boardman-Pretty, F., Boissiere, J. M., Boustred, C. R., Brittain, H., Caulfield, M. J., Chan, G. C., Craig, C. E. H., Daugherty, L. C., de Burca, A., Peterson, Kevin A, Devereau, A., Elgar, G., Foulger, R. E., Fowler, T., Furió-Tarí, P., Hackett, J. M., Halai, D., Hamblin, A., Henderson, S., Holman, J. E., Haselimashhadi, Hamed, Hubbard, T. J. P., Ibáñez, K., Jackson, R., Jones, L. J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S. E. A., Leong, I. U. S., Flenniken, Ann M, Lopez, F. J., Maleady-Crowe, F., Mason, J., McDonagh, E. M., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A. C., Odhams, C. A., Patch, C., Morgan, Hugh, Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Cacheiro, Pilar [0000-0002-6335-8208], Muñoz-Fuentes, Violeta [0000-0003-3574-546X], Nutter, Lauryl MJ [0000-0001-9619-146X], Peterson, Kevin A [0000-0001-8353-3694], Haselimashhadi, Hamed [0000-0001-7334-2421], Konopka, Tomasz [0000-0003-3042-4712], Hsu, Chih-Wei [0000-0002-9591-9567], Lanza, Denise G [0000-0001-8750-6933], Heaney, Jason D [0000-0001-8475-8828], Fuchs, Helmut [0000-0002-5143-2677], Gailus-Durner, Valerie [0000-0002-6076-0111], Lelliott, Christopher J [0000-0001-8087-4530], Adams, David J [0000-0001-9490-0306], Mammano, Fabio [0000-0003-3751-1691], McKerlie, Colin [0000-0002-2232-0967], Herault, Yann [0000-0001-7049-6900], de Angelis, Martin Hrabě [0000-0002-7898-2353], Lloyd, KC Kent [0000-0002-5318-4144], Smedley, Damian [0000-0002-5836-9850], Apollo - University of Cambridge Repository, Queen Mary University of London (QMUL), European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, The Jackson Laboratory [Bar Harbor] (JAX), Baylor College of Medicine (BCM), Baylor University, University of Pennsylvania, The Hospital for sick children [Toronto] (SickKids), Mount Sinai Hospital [Toronto, Canada] (MSH), MRC Harwell Institute [UK], Helmholtz Zentrum München = German Research Center for Environmental Health, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), Institute of Molecular Genetics of the Czech Academy of Sciences (IMG / CAS), Czech Academy of Sciences [Prague] (CAS), The Wellcome Trust Sanger Institute [Cambridge], Technische Universität München = Technical University of Munich (TUM), Ludwig-Maximilians-Universität München (LMU), CNR - Italian National Research Council (CNR), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg] (DZD), University of California [Davis] (UC Davis), University of California (UC), J C Ambrose, P Arumugam, E L Baple, M Bleda, F Boardman-Pretty, J M Boissiere, C R Boustred, H Brittain, M J Caulfield, G C Chan, C E H Craig, L C Daugherty, A de Burca, A Devereau, G Elgar, R E Foulger, T Fowler, P Furió-Tarí, J M Hackett, D Halai, A Hamblin, S Henderson, J E Holman, T J P Hubbard, K Ibáñez, R Jackson, L J Jones, D Kasperaviciute, M Kayikci, L Lahnstein, K Lawson, S E A Leigh, I U S Leong, F J Lopez, F Maleady-Crowe, J Mason, E M McDonagh, L Moutsianas, M Mueller, N Murugaesu, A C Need, C A Odhams, C Patch, D Perez-Gil, D Polychronopoulos, J Pullinger, T Rahim, A Rendon, P Riesgo-Ferreiro, T Rogers, M Ryten, K Savage, K Sawant, R H Scott, A Siddiq, A Sieghart, K R Smith, A Sosinsky, W Spooner, H E Stevens, A Stuckey, R Sultana, E R A Thomas, S R Thompson, C Tregidgo, A Tucci, E Walsh, S A Watters, M J Welland, E Williams, K Witkowska, S M Wood, M Zarowiecki, Susan Marschall, Christoph Lengger, Holger Maier, Claudia Seisenberger, Antje Bürger, Ralf Kühn, Joel Schick, Andreas Hörlein, Oskar Oritz, Florian Giesert, Joachim Beig, Janet Kenyon, Gemma Codner, Martin Fray, Sara J Johnson, James Cleak, Zsombor Szoke-Kovacs, David Lafont, Valerie E Vancollie, Robbie S B McLaren, Lena Hughes-Hallett, Christine Rowley, Emma Sanderson, Antonella Galli, Elizabeth Tuck, Angela Green, Catherine Tudor, Emma Siragher, Monika Dabrowska, Cecilia Icoresi Mazzeo, Mark Griffiths, David Gannon, Brendan Doe, Nicola Cockle, Andrea Kirton, Joanna Bottomley, Catherine Ingle, Edward Ryder, Diane Gleeson, Ramiro Ramirez-Solis, Marie-Christine Birling, Guillaume Pavlovic, Abdel Ayadi, Meziane Hamid, Ghina Bou About, Marie-France Champy, Hugues Jacobs, Olivia Wendling, Sophie Leblanc, Laurent Vasseur, Elissa J Chesler, Vivek Kumar, Jacqueline K White, Karen L Svenson, Jean-Paul Wiegand, Laura L Anderson, Troy Wilcox, James Clark, Jennifer Ryan, James Denegre, Tim Stearns, Vivek Philip, Catherine Witmeyer, Lindsay Bates, Zachary Seavey, Pamela Stanley, Amelia Willet, Willson Roper, Julie Creed, Michayla Moore, Alex Dorr, Pamelia Fraungruber, Rose Presby, Matthew Mckay, Dong Nguyen-Bresinsky, Leslie Goodwin, Rachel Urban, Coleen Kane, Herault, Yann, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
0301 basic medicine, Mutation rate, Cancer Research, [SDV]Life Sciences [q-bio], General Physics and Astronomy, methods [Genetic Association Studies], Disease, VARIANTS, Mice, Essential, 0302 clinical medicine, IMPC, Genetics research, Lethal allele, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, Organism, ComputingMilieux_MISCELLANEOUS, Disease gene, Mice, Knockout, 0303 health sciences, Multidisciplinary, Genes, Essential, genetics [Disease], Genomics, R/BIOCONDUCTOR PACKAGE, DATABASE, UPDATE, GENOME, [SDV] Life Sciences [q-bio], Knockout mouse, Identification (biology), ddc:500, International Mouse Phenotyping Consortium, Technology Platforms, Biotechnology, Knockout, Science, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Genetics, medicine, Animals, Humans, Genetic variation, Clinical genetics, Gene, Genetic Association Studies, 030304 developmental biology, Disease model, Prevention, Human Genome, General Chemistry, medicine.disease, Developmental disorder, Good Health and Well Being, 030104 developmental biology, Genomics England Research Consortium, Genes, lcsh:Q, Generic health relevance, 030217 neurology & neurosurgery, Rare disease
Abstract

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery., Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery.

Published
2020
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18. Roquin Paralogs 1 and 2 Redundantly Repress the Icos and Ox40 Costimulator mRNAs and Control Follicular Helper T Cell Differentiation

Author

Vogel, Katharina U., Edelmann, Stephanie L., Jeltsch, Katharina M., Bertossi, Arianna, Heger, Klaus, Heinz, Gitta A., Zöller, Jessica, Warth, Sebastian C., Hoefig, Kai P., Lohs, Claudia, Neff, Frauke, Kremmer, Elisabeth, Schick, Joel, Repsilber, Dirk, Geerlof, Arie, Blum, Helmut, Wurst, Wolfgang, Heikenwälder, Mathias, Schmidt-Supprian, Marc, and Heissmeyer, Vigo

Published
2013
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20. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling

Author

Kraft, Vanessa A. N., primary, Bezjian, Carla T., additional, Pfeiffer, Susanne, additional, Ringelstetter, Larissa, additional, Müller, Constanze, additional, Zandkarimi, Fereshteh, additional, Merl-Pham, Juliane, additional, Bao, Xuanwen, additional, Anastasov, Natasa, additional, Kössl, Johanna, additional, Brandner, Stefanie, additional, Daniels, Jacob D., additional, Schmitt-Kopplin, Philippe, additional, Hauck, Stefanie M., additional, Stockwell, Brent R., additional, Hadian, Kamyar, additional, and Schick, Joel A., additional

Published
2019
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23. Identification of genetic elements in metabolism by high-throughput mouse phenotyping

Author

Rozman, Jan, Rathkolb, Birgit, Meehan, Terrence F, Codner, Gemma F, Fiegel, Tanja, Ring, Natalie, Westerberg, Henrik, Greenaway, Simon, Sneddon, Duncan, Morgan, Hugh, Loeffler, Jorik, Stewart, Michelle E, Ramirez-Solis, Ramiro, Mason, Jeremy, Bradley, Allan, Skarnes, William C, Steel, Karen P, Maguire, Simon A, Dench, Joshua, Lafont, David, Vancollie, Valerie E, Pearson, Selina A, Gates, Amy S, Sanderson, Mark, Haselimashhadi, Hamed, Shannon, Carl, Anthony, Lauren F E, Sumowski, Maksymilian T, McLaren, Robbie S B, Doe, Brendan, Wardle-Jones, Hannah, Griffiths, Mark N D, Galli, Antonella, Swiatkowska, Agnieszka, Isherwood, Christopher M, Consortium, IMPC, Speak, Anneliese O, Cambridge, Emma L, Wilson, Heather M, Caetano, Susana S, Maguire, Anna Karin B, Adams, David J, Bottomley, Joanna, Ryder, Ed, Gleeson, Diane, Pouilly, Laurent, Hough, Tertius, Rousseau, Stephane, Auburtin, Aurélie, Reilly, Patrick, Ayadi, Abdel, Selloum, Mohammed, Wood, Joshua A, Clary, Dave, Havel, Peter, Tolentino, Todd, Tolentino, Heather, Mallon, Ann-Marie, Schuchbauer, Mike, Pedroia, Sheryl, Trainor, Amanda, Djan, Esi, Pham, Milton, Huynh, Alison, De Vera, Vincent, Seavitt, John, Gallegos, Juan, Garza, Arturo, Wells, Sara, Mangin, Elise, Senderstrom, Joel, Lazo, Iride, Mowrey, Kate, Bohat, Ritu, Samaco, Rodney, Veeraragavan, Surabi, Beeton, Christine, Kalaga, Sowmya, Kelsey, Lois, Santos, Luis, Vukobradovic, Igor, Berberovic, Zorana, Owen, Celeste, Qu, Dawei, Guo, Ruolin, Newbigging, Susan, Morikawa, Lily, Law, Napoleon, Shang, Xueyuan, Feugas, Patricia, Lelliott, Christopher J, Wang, Yanchun, Eskandarian, Mohammad, Zhu, Yingchun, Penton, Patricia, Laurin, Valerie, Clarke, Shannon, Lan, Qing, Sleep, Gillian, Creighton, Amie, Jacob, Elsa, White, Jacqueline K, Danisment, Ozge, Gertsenstein, Marina, Pereira, Monica, MacMaster, Suzanne, Tondat, Sandra, Carroll, Tracy, Cabezas, Jorge, Hunter, Jane, Clark, Greg, Bubshait, Mohammed, Oestereicher, Manuela A, Sorg, Tania, Miller, David, Sohel, Khondoker, Adissu, Hibret, Ganguly, Milan, Bezginov, Alexandr, Chiani, Francesco, Di Pietro, Chiara, Di Segni, Gianfranco, Ermakova, Olga, Ferrara, Filomena, Champy, Marie-France, Fruscoloni, Paolo, Gambadoro, Aalessia, Gastaldi, Serena, Golini, Elisabetta, La Sala, Gina, Mandillo, Silvia, Marazziti, Daniela, Massimi, Marzia, Matteoni, Rafaele, Orsini, Tiziana, Bower, Lynette R, Pasquini, Miriam, Raspa, Marcello, Rauch, Aline, Rossi, Gianfranco, Rossi, Nicoletta, Putti, Sabrina, Scavizzi, Ferdinando, Tocchini-Valentini, Giuseppe D, Wakana, Shigeharu, Suzuki, Tomohiro, Reynolds, Corey L, Tamura, Masaru, Kaneda, Hideki, Furuse, Tamio, Kobayashi, Kimio, Miura, Ikuo, Yamada, Ikuko, Obata, Yuichi, Yoshiki, Atsushi, Ayabe, Shinya, Chambers, J Nicole, Flenniken, Ann M, Chalupsky, Karel, Seisenberger, Claudia, Bürger, Antje, Beig, Joachim, Kühn, Ralf, Hörlein, Andreas, Schick, Joel, Oritz, Oskar, Giesert, Florian, Graw, Jochen, Murray, Stephen A, Ollert, Markus, Schmidt-Weber, Carsten, Stoeger, Tobias, Önder Yildirim, Ali, Eickelberg, Oliver, Klopstock, Thomas, Busch, Dirk H, Bekeredjian, Raffi, Zimmer, Andreas, Jacobsen, Jules O, Nutter, Lauryl M J, Smedley, Damian, Dickinson, Mary E, Benso, Frank, Morse, Iva, Kim, Hyoung-Chin, Lee, Ho, Cho, Soo Young, Svenson, Karen L, West, David, Tocchini-Valentini, Glauco P, Schütt, Christine, Beaudet, Arthur L, Bosch, Fatima, Braun, Robert B, Dobbie, Michael S, Gao, Xiang, Herault, Yann, Moshiri, Ala, Moore, Bret A, Kent Lloyd, K. C., McKerlie, Colin, Ravindranath, Aakash Chavan, Masuya, Hiroshi, Tanaka, Nobuhiko, Flicek, Paul, Parkinson, Helen E, Sedlacek, Radislav, Seong, Je Kyung, Wang, Chi-Kuang Leo, Moore, Mark, Brown, Steve D, Tschöp, Matthias H, Leuchtenberger, Stefanie, Wurst, Wolfgang, Klingenspor, Martin, Wolf, Eckhard, Beckers, Johannes, Machicao, Fausto, Peter, Andreas, Staiger, Harald, Häring, Hans-Ulrich, Grallert, Harald, Campillos, Monica, Sharma, Sapna, Maier, Holger, Fuchs, Helmut, Gailus-Durner, Valerie, Werner, Thomas, Hrabe de Angelis, Martin, Aguilar-Pimentel, Antonio, Becker, Lore, Treise, Irina, Moreth, Kristin, Garrett, Lillian, Kistler, Martin, Hölter, Sabine M, Zimprich, Annemarie, Marschall, Susan, Amarie, Oana V, Calzada-Wack, Julia, Neff, Frauke, Brachthäuser, Laura, Lengger, Christoph, Stoeger, Claudia, Zapf, Lilly, Willershäuser, Monja, Cho, Yi-Li, da Silva-Buttkus, Patricia, Kraiger, Markus J, Mayer-Kuckuk, Philipp, Gampe, Karen Kristine, Wu, Moya, Conte, Nathalie, Warren, Jonathan, Chen, Chao-Kung, Tudose, Ilinca, Brommage, Robert, Relac, Mike, Matthews, Peter, Cater, Heather L, Natukunda, Helen P, Cleak, James, Teboul, Lydia M, Clementson-Mobbs, Sharon, Szoke-Kovacs, Zsombor, Walling, Alison P, Johnson, Sara J, Rozman, Jan [0000-0002-8035-8904], Kistler, Martin [0000-0003-0116-7761], Mason, Jeremy [0000-0002-2796-5123], Lelliott, Christopher J [0000-0001-8087-4530], Herault, Yann [0000-0001-7049-6900], Kent Lloyd, KC [0000-0002-5318-4144], McKerlie, Colin [0000-0002-2232-0967], Flicek, Paul [0000-0002-3897-7955], Maier, Holger [0000-0003-2514-8290], Fuchs, Helmut [0000-0002-5143-2677], Hrabe de Angelis, Martin [0000-0002-7898-2353], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Blood Glucose, Candidate gene, Cancer Research, Basal Metabolism/genetics, Gene regulatory network, Obesity/genetics, genetics [Metabolic Diseases], General Physics and Astronomy, Genome-wide association study, Genome, Mice, genetics [Obesity], Triglycerides/metabolism, 2.1 Biological and endogenous factors, Gene Regulatory Networks, Aetiology, lcsh:Science, metabolism [Blood Glucose], Mice, Knockout, Multidisciplinary, genetics [Basal Metabolism], Phenotype, Area Under Curve, Diabetes Mellitus, Type 2/genetics, ddc:500, Technology Platforms, Type 2, metabolism [Triglycerides], Knockout, Science, Computational biology, Biology, genetics [Diabetes Mellitus, Type 2], General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Oxygen Consumption, Metabolic Diseases, Body Weight/genetics, Diabetes Mellitus, Genetics, Animals, Humans, Metabolic Diseases/genetics, Obesity, Gene, Gene knockout, Triglycerides, Oxygen Consumption/genetics, Blood Glucose/metabolism, genetics [Body Weight], Human Genome, Body Weight, Promoter, General Chemistry, genetics [Oxygen Consumption], High-Throughput Screening Assays, 030104 developmental biology, Diabetes Mellitus, Type 2, IMPC Consortium, lcsh:Q, Basal Metabolism, Genome-Wide Association Study
Abstract

Metabolic diseases are a worldwide problem but the underlying genetic factors and their relevance to metabolic disease remain incompletely understood. Genome-wide research is needed to characterize so-far unannotated mammalian metabolic genes. Here, we generate and analyze metabolic phenotypic data of 2016 knockout mouse strains under the aegis of the International Mouse Phenotyping Consortium (IMPC) and find 974 gene knockouts with strong metabolic phenotypes. 429 of those had no previous link to metabolism and 51 genes remain functionally completely unannotated. We compared human orthologues of these uncharacterized genes in five GWAS consortia and indeed 23 candidate genes are associated with metabolic disease. We further identify common regulatory elements in promoters of candidate genes. As each regulatory element is composed of several transcription factor binding sites, our data reveal an extensive metabolic phenotype-associated network of co-regulated genes. Our systematic mouse phenotype analysis thus paves the way for full functional annotation of the genome., The genetic basis of metabolic diseases is incompletely understood. Here, by high-throughput phenotyping of 2,016 knockout mouse strains, Rozman and colleagues identify candidate metabolic genes, many of which are associated with unexplored regulatory gene networks and metabolic traits in human GWAS.

Published
2018

24. Additional file 5: of ENCoRE: an efficient software for CRISPR screens identifies new players in extrinsic apoptosis

Author

TrĂźmbach, Dietrich, Pfeiffer, Susanne, Poppe, Manuel, Scherb, Hagen, Doll, Sebastian, Wurst, Wolfgang, and Schick, Joel

Abstract

Genotyping data for mutant cell lines. Individually generated mutations in mouse fibroblasts were amplified from genomic DNA, cloned, sequenced, and characterized for indels. For each gene primary sequencing data from the parental cell line (wild-type) are aligned with mutated sequences (KO) resulting in a frameshift mutation. The CRISPR guide sequences for engineering the mutations are also aligned (red). (PDF 949 kb)

Published
2017
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25. Additional file 4: of ENCoRE: an efficient software for CRISPR screens identifies new players in extrinsic apoptosis

Author

TrĂźmbach, Dietrich, Pfeiffer, Susanne, Poppe, Manuel, Scherb, Hagen, Doll, Sebastian, Wurst, Wolfgang, and Schick, Joel

Abstract

TNFa kill curve for CRISPR/Cas9 screening. Concentrations of soluble TNFa compared to cell survival 24Â h after addition to murine fibroblasts. Addition of the pan-caspase inhibitor zVAD demonstrates caspase-dependent cell death. (PDF 6 kb)

Published
2017
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26. Additional file 3: of ENCoRE: an efficient software for CRISPR screens identifies new players in extrinsic apoptosis

Author

TrĂźmbach, Dietrich, Pfeiffer, Susanne, Poppe, Manuel, Scherb, Hagen, Doll, Sebastian, Wurst, Wolfgang, and Schick, Joel

Abstract

Venn diagrams showing overlap of top 20 genes identified by different software ENCoRE, MAGeCK, and edgeR for two additional datasets, (A) Koike-Yusa, et al., [4] and (B) Bassett, et al., [21]. For both datasets, a comparable overlap of top genes is seen between pairs ENCoRE/MAGeCK and ENCoRE/edgeR as observed between MAGeCK/edgeR. (PDF 227 kb)

Published
2017
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27. Additional file 6: of ENCoRE: an efficient software for CRISPR screens identifies new players in extrinsic apoptosis

Author

TrĂźmbach, Dietrich, Pfeiffer, Susanne, Poppe, Manuel, Scherb, Hagen, Doll, Sebastian, Wurst, Wolfgang, and Schick, Joel

Abstract

ENCoRE validation on publicly available CRISPR screening data. (A) ENCoRE output from Bassett and colleagues [21] CRISPR viability screen in Drosophila S2R+ cells. At least two highly scoring genes emerged that implicate cell cycle control (Z600, FANCI) not seen in the original publication. (B) ENCoRE output from a CRISPR/Cas9 screen on mouse ESC cells from Li and colleagues [22] shows a similar profile of negatively selected genes and ZFP945 for positively selected genes, but differs in the identification of TRP53. (PDF 494 kb)

Published
2017
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28. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

Author

Bowl, Michael R., Simon, Michelle M., Ingham, Neil J., Greenaway, Simon, Santos, Luis, Cater, Heather, Taylor, Sarah, Mason, Jeremy, Kurbatova, Natalja, Pearson, Selina, Bower, Lynette R., Clary, Dave A., Meziane, Hamid, Reilly, Patrick, Minowa, Osamu, Kelsey, Lois, Allen, Sue, Clementson-Mobbs, Sharon, Codner, Gemma, Fray, Martin, Gardiner, Wendy, Joynson, Russell, Kenyon, Janet, Loeffler, Jorik, Nell, Barbara, Parker, Andrew, Quwailid, Deen, Stewart, Michelle, Walling, Alison, Zaman, Rumana, Chen, Chao Kung, Conte, Nathalie, Matthews, Peter, Relac, Mike, Tudose, Ilinca, Warren, Jonathan, Le Marchand, Elise, El Amri, Amal, El Fertak, Leila, Ennah, Hamid, Ali-Hadji, Dalila, Ayadi, Abdel, Wattenhofer-Donze, Marie, Moulaert, David, Jacquot, Sylvie, André, Philippe, Birling, Marie Christine, Pavlovic, Guillaume, Lalanne, Valérie, Lux, Aline, Riet, Fabrice, Mittelhaeuser, Christophe, Bour, Raphael, Guimond, Alain, Bam'Hamed, Chaouki, Leblanc, Sophie, Vasseur, Laurent, Selloum, Mohammed, Sorg, Tania, Ayabe, Shinya, Furuse, Tamio, Kaneda, Hideki, Kobayashi, Kimio, Masuya, Hiroshi, Miura, Ikuo, Obata, Yuichi, Suzuki, Tomohiro, Tamura, Masaru, Tanaka, Nobuhiko, Yamada, Ikuko, Yoshiki, Atsushi, Berberovic, Zorana, Bubshait, Mohammed, Cabezas, Jorge, Carroll, Tracy, Clark, Greg, Clarke, Shannon, Creighton, Amie, Danisment, Ozge, Eskandarian, Mohammad, Feugas, Patricia, Gertsenstein, Marina, Guo, Ruolin, Hunter, Jane, Jacob, Elsa, Lan, Qing, Laurin, Valerie, Law, Napoleon, MacMaster, Sue, Miller, David, Morikawa, Lily, Newbigging, Susan, Owen, Celeste, Penton, Patricia, Pereira, Monica, Qu, Dawei, Shang, Xueyuan, Sleep, Gillian, Sohel, Khondoker, Tondat, Sandra, Wang, Yanchun, Vukobradovic, Igor, Zhu, Yingchun, Chiani, Francesco, Di Pietro, Chiara, Di Segni, Gianfranco, Ermakova, Olga, Ferrara, Filomena, Fruscoloni, Paolo, Gambadoro, Aalessia, Gastaldi, Serena, Golini, Elisabetta, Sala, Gina La, Mandillo, Silvia, Marazziti, Daniela, Massimi, Marzia, Matteoni, Rafaele, Orsini, Tiziana, Pasquini, Miriam, Raspa, Marcello, Rauch, Aline, Rossi, Gianfranco, Rossi, Nicoletta, Putti, Sabrina, Scavizzi, Ferdinando, Tocchini-Valentini, Giuseppe D., Beig, Joachim, Bürger, Antje, Giesert, Florian, Graw, Jochen, Kühn, Ralf, Oritz, Oskar, Schick, Joel, Seisenberger, Claudia, Amarie, Oana, Garrett, Lillian, Hölter, Sabine M., Zimprich, Annemarie, Aguilar-Pimentel, Antonio, Beckers, Johannes, Brommage, Robert, Calzada-Wack, Julia, Fuchs, Helmut, Gailus-Durner, Valérie, Lengger, Christoph, Leuchtenberger, Stefanie, Maier, Holger, Marschall, Susan, Moreth, Kristin, Neff, Frauke, Östereicher, Manuela A., Rozman, Jan, Steinkamp, Ralph, Stoeger, Claudia, Treise, Irina, Stoeger, Tobias, Yildrim, Ali Önder, Eickelberg, Oliver, Becker, Lore, Klopstock, Thomas, Ollert, Markus, Busch, Dirk H., Schmidt-Weber, Carsten, Bekeredjian, Raffi, Zimmer, Andreas, Rathkolb, Birgit, Wolf, Eckhard, Klingenspor, Martin, Tocchini-Valentini, Glauco P., Gao, Xiang, Bradley, Allan, Skarnes, William C., Moore, Mark, Beaudet, Arthur L., Justice, Monica J., Seavitt, John, Dickinson, Mary E., Wurst, Wolfgang, De Angelis, Martin Hrabe, Herault, Yann, Wakana, Shigeharu, Nutter, Lauryl M.J., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Svenson, Karen L., Braun, Robert E., West, David B., Lloyd, K. C.Kent, Adams, David J., White, Jacqui, Karp, Natasha, Flicek, Paul, Smedley, Damian, Meehan, Terrence F., Parkinson, Helen E., Teboul, Lydia M., Wells, Sara, Steel, Karen P., Mallon, Ann Marie, Brown, Steve D.M., Mason, Jeremy [0000-0002-2796-5123], de Angelis, Martin Hrabe [0000-0002-7898-2353], Herault, Yann [0000-0001-7049-6900], Wakana, Shigeharu [0000-0001-8532-0924], McKerlie, Colin [0000-0002-2232-0967], Lloyd, KC Kent [0000-0002-5318-4144], Flicek, Paul [0000-0002-3897-7955], Smedley, Damian [0000-0002-5836-9850], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Cancer Research, Candidate gene, General Physics and Astronomy, Datasets as Topic, Mice, 2.1 Biological and endogenous factors, Protein Interaction Maps, Aetiology, lcsh:Science, Pediatric, Genetics, Mice, Knockout, Multidisciplinary, medicine.diagnostic_test, Hearing Tests, Ear, Phenotype, medicine.anatomical_structure, Technology Platforms, International Mouse Phenotyping Consortium, medicine.symptom, Biotechnology, Hearing Loss/epidemiology, Hearing loss, Knockout, 1.1 Normal biological development and functioning, Science, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Clinical Research, Underpinning research, medicine, otorhinolaryngologic diseases, Auditory system, Animals, Genetic Testing, IMPC, mouse, auditory dysfunction, Set (psychology), Hearing Loss, Gene, Genetic testing, Auditory dysfunction, Human Genome, General Chemistry, 030104 developmental biology, Protein Interaction Maps/genetics, lcsh:Q
Abstract

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function., The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Published
2017

29. Additional file 2: of ENCoRE: an efficient software for CRISPR screens identifies new players in extrinsic apoptosis

Author

TrĂźmbach, Dietrich, Pfeiffer, Susanne, Poppe, Manuel, Scherb, Hagen, Doll, Sebastian, Wurst, Wolfgang, and Schick, Joel

Subjects
Hardware_MEMORYSTRUCTURES, TheoryofComputation_COMPUTATIONBYABSTRACTDEVICES, ComputerSystemsOrganization_COMPUTERSYSTEMIMPLEMENTATION, Software_PROGRAMMINGTECHNIQUES, ComputerSystemsOrganization_PROCESSORARCHITECTURES
Abstract

The ENCoRE Quick Guide for downloading and processing CRISPR screens with ENCoRE. (PDF 942 kb)

Published
2017
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31. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition

Author

Doll, Sebastian, primary, Proneth, Bettina, additional, Tyurina, Yulia Y, additional, Panzilius, Elena, additional, Kobayashi, Sho, additional, Ingold, Irina, additional, Irmler, Martin, additional, Beckers, Johannes, additional, Aichler, Michaela, additional, Walch, Axel, additional, Prokisch, Holger, additional, Trümbach, Dietrich, additional, Mao, Gaowei, additional, Qu, Feng, additional, Bayir, Hulya, additional, Füllekrug, Joachim, additional, Scheel, Christina H, additional, Wurst, Wolfgang, additional, Schick, Joel A, additional, Kagan, Valerian E, additional, Angeli, José Pedro Friedmann, additional, and Conrad, Marcus, additional

Published
2016
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32. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling

Author

Kraft, Vanessa A. N., Bezjian, Carla T., Pfeiffer, Susanne, Ringelstetter, Larissa, Müller, Constanze, Zandkarimi, Fereshteh, Merl-Pham, Juliane, Bao, Xuanwen, Anastasov, Natasa, Kössl, Johanna, Brandner, Stefanie, Daniels, Jacob D., Schmitt-Kopplin, Philippe, Hauck, Stefanie M., Stockwell, Brent R., Hadian, Kamyar, and Schick, Joel A.

Abstract

Ferroptosis is an iron-dependent form of regulated cell death linking iron, lipid, and glutathione levels to degenerative processes and tumor suppression. By performing a genome-wide activation screen, we identified a cohort of genes antagonizing ferroptotic cell death, including GTP cyclohydrolase-1 (GCH1) and its metabolic derivatives tetrahydrobiopterin/dihydrobiopterin (BH4/BH2). Synthesis of BH4/BH2by GCH1-expressing cells caused lipid remodeling, suppressing ferroptosis by selectively preventing depletion of phospholipids with two polyunsaturated fatty acyl tails. GCH1 expression level in cancer cell lines stratified susceptibility to ferroptosis, in accordance with its expression in human tumor samples. The GCH1-BH4-phospholipid axis acts as a master regulator of ferroptosis resistance, controlling endogenous production of the antioxidant BH4, abundance of CoQ10, and peroxidation of unusual phospholipids with two polyunsaturated fatty acyl tails. This demonstrates a unique mechanism of ferroptosis protection that is independent of the GPX4/glutathione system.

Published
2020
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33. CRISPR-Cas9 enables conditional mutagenesis of challenging loci

Author

Schick, Joel A., primary, Seisenberger, Claudia, additional, Beig, Joachim, additional, Bürger, Antje, additional, Iyer, Vivek, additional, Maier, Viola, additional, Perera, Sajith, additional, Rosen, Barry, additional, Skarnes, William C., additional, and Wurst, Wolfgang, additional

Published
2016
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35. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice

Author

Friedmann Angeli, Jose Pedro, primary, Schneider, Manuela, additional, Proneth, Bettina, additional, Tyurina, Yulia Y., additional, Tyurin, Vladimir A., additional, Hammond, Victoria J., additional, Herbach, Nadja, additional, Aichler, Michaela, additional, Walch, Axel, additional, Eggenhofer, Elke, additional, Basavarajappa, Devaraj, additional, Rådmark, Olof, additional, Kobayashi, Sho, additional, Seibt, Tobias, additional, Beck, Heike, additional, Neff, Frauke, additional, Esposito, Irene, additional, Wanke, Rüdiger, additional, Förster, Heidi, additional, Yefremova, Olena, additional, Heinrichmeyer, Marc, additional, Bornkamm, Georg W., additional, Geissler, Edward K., additional, Thomas, Stephen B., additional, Stockwell, Brent R., additional, O’Donnell, Valerie B., additional, Kagan, Valerian E., additional, Schick, Joel A., additional, and Conrad, Marcus, additional

Published
2014
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36. Direct Cloning of Isogenic Murine DNA in Yeast and Relevance of Isogenicity for Targeting in Embryonic Stem Cells

Author

Andreasson, Claes, Schick, Anna J., Pfeiffer, Susanne M., Sarov, Mihail, Stewart, Francis, Wurst, Wolfgang, Schick, Joel A., Andreasson, Claes, Schick, Anna J., Pfeiffer, Susanne M., Sarov, Mihail, Stewart, Francis, Wurst, Wolfgang, and Schick, Joel A.

Abstract

Efficient gene targeting in embryonic stem cells requires that modifying DNA sequences are identical to those in the targeted chromosomal locus. Yet, there is a paucity of isogenic genomic clones for human cell lines and PCR amplification cannot be used in many mutation-sensitive applications. Here, we describe a novel method for the direct cloning of genomic DNA into a targeting vector, pRTVIR, using oligonucleotide-directed homologous recombination in yeast. We demonstrate the applicability of the method by constructing functional targeting vectors for mammalian genes Uhrf1 and Gfap. Whereas the isogenic targeting of the gene Uhrf1 showed a substantial increase in targeting efficiency compared to non-isogenic DNA in mouse E14 cells, E14-derived DNA performed better than the isogenic DNA in JM8 cells for both Uhrf1 and Gfap. Analysis of 70 C57BL/6-derived targeting vectors electroporated in JM8 and E14 cell lines in parallel showed a clear dependence on isogenicity for targeting, but for three genes isogenic DNA was found to be inhibitory. In summary, this study provides a straightforward methodological approach for the direct generation of isogenic gene targeting vectors., AuthorCount:7

Published
2013
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37. Roquin paralogs 1 and 2 redundantly repress the Icos and Ox40 costimulator mRNAs and control follicular helper T cell differentiation

Author

Vogel, Katharina U, Edelmann, Stephanie L, Jeltsch, Katharina M, Bertossi, Arianna, Heger, Klaus, Heinz, Gitta A, Zöller, Jessica, Warth, Sebastian C, Hoefig, Kai P, Lohs, Claudia, Neff, Frauke, Kremmer, Elisabeth, Schick, Joel, Repsilber, Dirk, Geerlof, Arie, Blum, Helmut, Wurst, Wolfgang, Heikenwälder, Mathias, Schmidt-Supprian, Marc, Heissmeyer, Vigo, Vogel, Katharina U, Edelmann, Stephanie L, Jeltsch, Katharina M, Bertossi, Arianna, Heger, Klaus, Heinz, Gitta A, Zöller, Jessica, Warth, Sebastian C, Hoefig, Kai P, Lohs, Claudia, Neff, Frauke, Kremmer, Elisabeth, Schick, Joel, Repsilber, Dirk, Geerlof, Arie, Blum, Helmut, Wurst, Wolfgang, Heikenwälder, Mathias, Schmidt-Supprian, Marc, and Heissmeyer, Vigo

Abstract

The Roquin-1 protein binds to messenger RNAs (mRNAs) and regulates gene expression posttranscriptionally. A single point mutation in Roquin-1, but not gene ablation, increases follicular helper T (Tfh) cell numbers and causes lupus-like autoimmune disease in mice. In T cells, we did not identify a unique role for the much lower expressed paralog Roquin-2. However, combined ablation of both genes induced accumulation of T cells with an effector and follicular helper phenotype. We showed that Roquin-1 and Roquin-2 proteins redundantly repressed the mRNA of inducible costimulator (Icos) and identified the Ox40 costimulatory receptor as another shared mRNA target. Combined acute deletion increased Ox40 signaling, as well as Irf4 expression, and imposed Tfh differentiation on CD4(+) T cells. These data imply that both proteins maintain tolerance by preventing inappropriate T cell activation and Tfh cell differentiation, and that Roquin-2 compensates in the absence of Roquin-1, but not in the presence of its mutated form.

Published
2013
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39. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition

Author

Doll, Sebastian, Proneth, Bettina, Tyurina, Yulia Y, Panzilius, Elena, Kobayashi, Sho, Ingold, Irina, Irmler, Martin, Beckers, Johannes, Aichler, Michaela, Walch, Axel, Prokisch, Holger, Trümbach, Dietrich, Mao, Gaowei, Qu, Feng, Bayir, Hulya, Füllekrug, Joachim, Scheel, Christina H, Wurst, Wolfgang, Schick, Joel A, Kagan, Valerian E, Angeli, José Pedro Friedmann, and Conrad, Marcus

Abstract

Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches—a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines—to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4–Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.

Published
2017
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