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4. Genetic predisposition to neuroblastoma results from a regulatory polymorphism that promotes the adrenergic cell state

Author

Weichert-Leahey, Nina, Shi, Hui, Tao, Ting, Oldridge, Derek A., Durbin, Adam D., Abraham, Brian J., Zimmerman, Mark W., Zhu, Shizhen, Wood, Andrew C., Reyon, Deepak, Joung, J. Keith, Young, Richard A., Diskin, Sharon J., Maris, John M., and Look, A. Thomas

Subjects
Adrenergic mechanisms -- Genetic aspects -- Health aspects, Stem cells -- Genetic aspects -- Health aspects, Single nucleotide polymorphisms -- Research, Neuroblastoma -- Genetic aspects -- Risk factors -- Development and progression, Pediatric research, Health care industry
Abstract

Childhood neuroblastomas exhibit plasticity between an undifferentiated neural crest-like mesenchymal cell state and a more differentiated sympathetic adrenergic cell state. These cell states are governed by autoregulatory transcriptional loops called core regulatory circuitries (CRCs), which drive the early development of sympathetic neuronal progenitors from migratory neural crest cells during embryogenesis. The adrenergic cell identity of neuroblastoma requires LMO1 as a transcriptional cofactor. Both LMO1 expression levels and the risk of developing neuroblastoma in children are associated with a single nucleotide polymorphism, G/T, that affects a GATA motif in the first intron of LMO1. Here, we showed that WT zebrafish with the GATA genotype developed adrenergic neuroblastoma, while knock-in of the protective TATA allele at this locus reduced the penetrance of MYCN-driven tumors, which were restricted to the mesenchymal cell state. Whole genome sequencing of childhood neuroblastomas demonstrated that TATA/TATA tumors also exhibited a mesenchymal cell state and were low risk at diagnosis. Thus, conversion of the regulatory GATA to a TATA allele in the first intron of LMO1 reduced the neuroblastoma-initiation rate by preventing formation of the adrenergic cell state. This mechanism was conserved over 400 million years of evolution, separating zebrafish and humans., Introduction Across all cell lineages and tissue types, groups of transcription factors act cooperatively in autoregulatory loops to bind to their own and each other's enhancers to regulate gene expression, [...]

Published
2023
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6. Discovery of widespread type I and type V CRISPR-Cas inhibitors

Author

Marino, Nicole D, Zhang, Jenny Y, Borges, Adair L, Sousa, Alexander A, Leon, Lina M, Rauch, Benjamin J, Walton, Russell T, Berry, Joel D, Joung, J Keith, Kleinstiver, Benjamin P, and Bondy-Denomy, Joseph

Subjects
Aetiology, 2.1 Biological and endogenous factors, Bacterial Proteins, CRISPR-Cas Systems, Cell Line, Computational Biology, Endonucleases, Gene Editing, Humans, Moraxella, Pseudomonas, General Science & Technology
Abstract

Bacterial CRISPR-Cas systems protect their host from bacteriophages and other mobile genetic elements. Mobile elements, in turn, encode various anti-CRISPR (Acr) proteins to inhibit the immune function of CRISPR-Cas. To date, Acr proteins have been discovered for type I (subtypes I-D, I-E, and I-F) and type II (II-A and II-C) but not other CRISPR systems. Here, we report the discovery of 12 acr genes, including inhibitors of type V-A and I-C CRISPR systems. AcrVA1 inhibits a broad spectrum of Cas12a (Cpf1) orthologs-including MbCas12a, Mb3Cas12a, AsCas12a, and LbCas12a-when assayed in human cells. The acr genes reported here provide useful biotechnological tools and mark the discovery of acr loci in many bacteria and phages.

Published
2018

10. Enhanced proofreading governs CRISPR–Cas9 targeting accuracy

Author

Chen, Janice S, Dagdas, Yavuz S, Kleinstiver, Benjamin P, Welch, Moira M, Sousa, Alexander A, Harrington, Lucas B, Sternberg, Samuel H, Joung, J Keith, Yildiz, Ahmet, and Doudna, Jennifer A

Subjects
Engineering, Electrical Engineering, Physical Sciences, Biotechnology, CRISPR-Associated Proteins, CRISPR-Cas Systems, Endonucleases, Enzyme Activation, Gene Editing, Genetic Variation, Humans, Mutagenesis, Protein Domains, Streptococcus pyogenes, Substrate Specificity, General Science & Technology
Abstract

The RNA-guided CRISPR-Cas9 nuclease from Streptococcus pyogenes (SpCas9) has been widely repurposed for genome editing. High-fidelity (SpCas9-HF1) and enhanced specificity (eSpCas9(1.1)) variants exhibit substantially reduced off-target cleavage in human cells, but the mechanism of target discrimination and the potential to further improve fidelity are unknown. Here, using single-molecule Förster resonance energy transfer experiments, we show that both SpCas9-HF1 and eSpCas9(1.1) are trapped in an inactive state when bound to mismatched targets. We find that a non-catalytic domain within Cas9, REC3, recognizes target complementarity and governs the HNH nuclease to regulate overall catalytic competence. Exploiting this observation, we design a new hyper-accurate Cas9 variant (HypaCas9) that demonstrates high genome-wide specificity without compromising on-target activity in human cells. These results offer a more comprehensive model to rationalize and modify the balance between target recognition and nuclease activation for precision genome editing.

Published
2017

15. Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma

Author

Saha, Supriya K, Gordan, John D, Kleinstiver, Benjamin P, Vu, Phuong, Najem, Mortada S, Yeo, Jia-Chi, Shi, Lei, Kato, Yasutaka, Levin, Rebecca S, Webber, James T, Damon, Leah J, Egan, Regina K, Greninger, Patricia, McDermott, Ultan, Garnett, Mathew J, Jenkins, Roger L, Rieger-Christ, Kimberly M, Sullivan, Travis B, Hezel, Aram F, Liss, Andrew S, Mizukami, Yusuke, Goyal, Lipika, Ferrone, Cristina R, Zhu, Andrew X, Joung, J Keith, Shokat, Kevan M, Benes, Cyril H, and Bardeesy, Nabeel

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Digestive Diseases - (Gallbladder), Cancer, Liver Disease, Orphan Drug, Liver Cancer, Digestive Diseases, Rare Diseases, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Bile Duct Neoplasms, Cell Line, Tumor, Cell Proliferation, Cholangiocarcinoma, Cluster Analysis, Dasatinib, Disease Models, Animal, Drug Resistance, Neoplasm, Gene Expression Profiling, Humans, Isocitrate Dehydrogenase, Mice, Mutation, Xenograft Model Antitumor Assays, src-Family Kinases, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

UnlabelledIntrahepatic cholangiocarcinoma (ICC) is an aggressive liver bile duct malignancy exhibiting frequent isocitrate dehydrogenase (IDH1/IDH2) mutations. Through a high-throughput drug screen of a large panel of cancer cell lines, including 17 biliary tract cancers, we found that IDH mutant (IDHm) ICC cells demonstrate a striking response to the multikinase inhibitor dasatinib, with the highest sensitivity among 682 solid tumor cell lines. Using unbiased proteomics to capture the activated kinome and CRISPR/Cas9-based genome editing to introduce dasatinib-resistant "gatekeeper" mutant kinases, we identified SRC as a critical dasatinib target in IDHm ICC. Importantly, dasatinib-treated IDHm xenografts exhibited pronounced apoptosis and tumor regression. Our results show that IDHm ICC cells have a unique dependency on SRC and suggest that dasatinib may have therapeutic benefit against IDHm ICC. Moreover, these proteomic and genome-editing strategies provide a systematic and broadly applicable approach to define targets of kinase inhibitors underlying drug responsiveness.SignificanceIDH mutations define a distinct subtype of ICC, a malignancy that is largely refractory to current therapies. Our work demonstrates that IDHm ICC cells are hypersensitive to dasatinib and critically dependent on SRC activity for survival and proliferation, pointing to new therapeutic strategies against these cancers. Cancer Discov; 6(7); 727-39. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.

Published
2016

20. High-resolution CTCF footprinting reveals impact of chromatin state on cohesin extrusion dynamics

Author

Sept, Corriene E., primary, Tak, Y. Esther, additional, Cerda-Smith, Christian G., additional, Hutchinson, Haley M., additional, Goel, Viraat, additional, Blanchette, Marco, additional, Bhakta, Mital S., additional, Hansen, Anders S., additional, Joung, J. Keith, additional, Johnstone, Sarah, additional, Eyler, Christine E., additional, and Aryee, Martin J., additional

Published
2023
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23. Gene therapy comes of age

Author

Dunbar, Cynthia E., High, Katherine A., Joung, J. Keith, Kohn, Donald B., Ozawa, Keiya, and Sadelain, Michel

Published
2018

25. Transcriptome-wide off-target RNA editing induced by CRISPR-guided DNA base editors

Author

Grünewald, Julian, Zhou, Ronghao, Garcia, Sara P., Iyer, Sowmya, Lareau, Caleb A., Aryee, Martin J., and Joung, J. Keith

Subjects
RNA processing -- Methods -- Analysis, CRISPR-Cas technology -- Usage, Cytosine -- Genetic aspects -- Usage, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

CRISPR-Cas base-editor technology enables targeted nucleotide alterations, and is being increasingly used for research and potential therapeutic applications.sup.1,2. The most widely used cytosine base editors (CBEs) induce deamination of DNA cytosines using the rat APOBEC1 enzyme, which is targeted by a linked Cas protein-guide RNA complex.sup.3,4. Previous studies of the specificity of CBEs have identified off-target DNA edits in mammalian cells.sup.5,6. Here we show that a CBE with rat APOBEC1 can cause extensive transcriptome-wide deamination of RNA cytosines in human cells, inducing tens of thousands of C-to-U edits with frequencies ranging from 0.07% to 100% in 38-58% of expressed genes. CBE-induced RNA edits occur in both protein-coding and non-protein-coding sequences and generate missense, nonsense, splice site, and 5' and 3' untranslated region mutations. We engineered two CBE variants bearing mutations in rat APOBEC1 that substantially decreased the number of RNA edits (by more than 390-fold and more than 3,800-fold) in human cells. These variants also showed more precise on-target DNA editing than the wild-type CBE and, for most guide RNAs tested, no substantial reduction in editing efficiency. Finally, we show that an adenine base editor.sup.7 can also induce transcriptome-wide RNA edits. These results have implications for the use of base editors in both research and clinical settings, illustrate the feasibility of engineering improved variants with reduced RNA editing activities, and suggest the need to more fully define and characterize the RNA off-target effects of deaminase enzymes in base editor platforms. CRISPR DNA base editors induce transcriptome-wide off-target RNA editing, which can be reduced by using engineered variants that retain on-target DNA editing activities., Author(s): Julian Grünewald [sup.1] [sup.2] [sup.3] [sup.4] , Ronghao Zhou [sup.1] [sup.2] [sup.3] , Sara P. Garcia [sup.1] , Sowmya Iyer [sup.1] , Caleb A. Lareau [sup.1] [sup.5] , Martin [...]

Published
2019
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28. Adopt a moratorium on heritable genome editing

Author

Lander, Eric S., Baylis, Françoise, Zhang, Feng, Charpentier, Emmanuelle, Berg, Paul, Bourgain, Catherine, Friedrich, Bärbel, Joung, J. Keith, Li, Jinsong, Liu, David, Naldini, Luigi, Nie, Jing-Bao, Qiu, Renzong, Schoene-Seifert, Bettina, Shao, Feng, Terry, Sharon, Wei, Wensheng, and Winnacker, Ernst-Ludwig

Published
2019
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32. Gene editing without ex vivo culture evades genotoxicity in human hematopoietic stem cells

Author

Zeng, Jing, primary, Nguyen, My Anh, additional, Liu, Pengpeng, additional, Ferreira da Silva, Lucas, additional, Lin, Linda Y, additional, Justus, David G, additional, Petri, Karl, additional, Clement, Kendell, additional, Porter, Shaina N, additional, Verma, Archana, additional, Neri, Nola R, additional, Rosanwo, Tolulope, additional, Ciuculescu, Marioara-Felicia, additional, Abriss, Daniela, additional, Mintzer, Esther, additional, Maitland, Stacy A, additional, Demirci, Selami, additional, Tisdale, John F, additional, Williams, David A, additional, Zhu, Lihua Julie, additional, Pruett-Miller, Shondra M, additional, Pinello, Luca, additional, Joung, J. Keith, additional, Pattanayak, Vikram, additional, Manis, John P, additional, Armant, Myriam, additional, Pellin, Danilo, additional, Brendel, Christian, additional, Wolfe, Scot A, additional, and Bauer, Daniel E, additional

Published
2023
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37. In vivo CRISPR editing with no detectable genome-wide off-target mutations

Author

Akcakaya, Pinar, Bobbin, Maggie L., Guo, Jimmy A., Malagon-Lopez, Jose, Clement, Kendell, Garcia, Sara P., Fellows, Mick D., Porritt, Michelle J., Firth, Mike A., Carreras, Alba, Baccega, Tania, Seeliger, Frank, Bjursell, Mikael, Tsai, Shengdar Q., Nguyen, Nhu T., Nitsch, Roberto, Mayr, Lorenz M., Pinello, Luca, Bohlooly-Y, Mohammad, Aryee, Martin J., Maresca, Marcello, and Joung, J. Keith

Published
2018
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39. Supplementary Table S1 from Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma

Author

Saha, Supriya K., primary, Gordan, John D., primary, Kleinstiver, Benjamin P., primary, Vu, Phuong, primary, Najem, Mortada S., primary, Yeo, Jia-Chi, primary, Shi, Lei, primary, Kato, Yasutaka, primary, Levin, Rebecca S., primary, Webber, James T., primary, Damon, Leah J., primary, Egan, Regina K., primary, Greninger, Patricia, primary, McDermott, Ultan, primary, Garnett, Mathew J., primary, Jenkins, Roger L., primary, Rieger-Christ, Kimberly M., primary, Sullivan, Travis B., primary, Hezel, Aram F., primary, Liss, Andrew S., primary, Mizukami, Yusuke, primary, Goyal, Lipika, primary, Ferrone, Cristina R., primary, Zhu, Andrew X., primary, Joung, J. Keith, primary, Shokat, Kevan M., primary, Benes, Cyril H., primary, and Bardeesy, Nabeel, primary

Published
2023
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40. Data from Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma

Author

Saha, Supriya K., primary, Gordan, John D., primary, Kleinstiver, Benjamin P., primary, Vu, Phuong, primary, Najem, Mortada S., primary, Yeo, Jia-Chi, primary, Shi, Lei, primary, Kato, Yasutaka, primary, Levin, Rebecca S., primary, Webber, James T., primary, Damon, Leah J., primary, Egan, Regina K., primary, Greninger, Patricia, primary, McDermott, Ultan, primary, Garnett, Mathew J., primary, Jenkins, Roger L., primary, Rieger-Christ, Kimberly M., primary, Sullivan, Travis B., primary, Hezel, Aram F., primary, Liss, Andrew S., primary, Mizukami, Yusuke, primary, Goyal, Lipika, primary, Ferrone, Cristina R., primary, Zhu, Andrew X., primary, Joung, J. Keith, primary, Shokat, Kevan M., primary, Benes, Cyril H., primary, and Bardeesy, Nabeel, primary

Published
2023
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41. Supplementary Figure Legends, Figures S1 - S6 from Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma

Author

Saha, Supriya K., primary, Gordan, John D., primary, Kleinstiver, Benjamin P., primary, Vu, Phuong, primary, Najem, Mortada S., primary, Yeo, Jia-Chi, primary, Shi, Lei, primary, Kato, Yasutaka, primary, Levin, Rebecca S., primary, Webber, James T., primary, Damon, Leah J., primary, Egan, Regina K., primary, Greninger, Patricia, primary, McDermott, Ultan, primary, Garnett, Mathew J., primary, Jenkins, Roger L., primary, Rieger-Christ, Kimberly M., primary, Sullivan, Travis B., primary, Hezel, Aram F., primary, Liss, Andrew S., primary, Mizukami, Yusuke, primary, Goyal, Lipika, primary, Ferrone, Cristina R., primary, Zhu, Andrew X., primary, Joung, J. Keith, primary, Shokat, Kevan M., primary, Benes, Cyril H., primary, and Bardeesy, Nabeel, primary

Published
2023
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42. Genetic Predisposition to Neuroblastoma Results from a Regulatory Polymorphism that Promotes the Adrenergic Cell State

Author

Weichert-Leahey, Nina, primary, Shi, Hui, additional, Tao, Ting, additional, Oldridge, Derek A, additional, Durbin, Adam D, additional, Abraham, Brian J., additional, Zimmerman, Mark W, additional, Zhu, Shizhen, additional, Wood, Andrew C, additional, Reyon, Deepak, additional, Joung, J Keith, additional, Young, Richard A, additional, Diskin, Sharon J, additional, Maris, John M., additional, and Look, A Thomas, additional

Published
2023
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44. High levels of AAV vector integration into CRISPR-induced DNA breaks

Author

Hanlon, Killian S., Kleinstiver, Benjamin P., Garcia, Sara P., Zaborowski, Mikołaj P., Volak, Adrienn, Spirig, Stefan E., Muller, Alissa, Sousa, Alexander A., Tsai, Shengdar Q., Bengtsson, Niclas E., Lööv, Camilla, Ingelsson, Martin, Chamberlain, Jeffrey S., Corey, David P., Aryee, Martin J., Joung, J. Keith, Breakefield, Xandra O., Maguire, Casey A., and György, Bence

Published
2019
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45. Enhanced proofreading governs CRISPRCas9 targeting accuracy

Author

Chen, Janice S., Dagdas, Yavuz S., Kleinstiver, Benjamin P., Welch, Moira M., Sousa, Alexander A., Harrington, Lucas B., Sternberg, Samuel H., Joung, J. Keith, Yildiz, Ahmet, and Doudna, Jennifer A.

Subjects
RNA sequencing -- Methods, Streptococcus pyogenes -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Janice S. Chen [1]; Yavuz S. Dagdas [2]; Benjamin P. Kleinstiver [3, 4, 5]; Moira M. Welch [3, 4]; Alexander A. Sousa [3, 4]; Lucas B. Harrington [1]; Samuel [...]

Published
2017
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