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3. Brain-region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice

Author

Farsi, Zohreh, Nicolella, Ally, Simmons, Sean K., Aryal, Sameer, Shepard, Nate, Brenner, Kira, Lin, Sherry, Herzog, Linnea, Moran, Sean P., Stalnaker, Katherine J., Shin, Wangyong, Gazestani, Vahid, Song, Bryan J., Bonanno, Kevin, Keshishian, Hasmik, Carr, Steven A., Pan, Jen Q., Macosko, Evan Z., Datta, Sandeep Robert, Dejanovic, Borislav, Kim, Eunjoon, Levin, Joshua Z., and Sheng, Morgan

Published
2023
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5. Single-Cell Profiles of Retinal Ganglion Cells Differing in Resilience to Injury Reveal Neuroprotective Genes

Author

Tran, Nicholas M, Shekhar, Karthik, Whitney, Irene E, Jacobi, Anne, Benhar, Inbal, Hong, Guosong, Yan, Wenjun, Adiconis, Xian, Arnold, McKinzie E, Lee, Jung Min, Levin, Joshua Z, Lin, Dingchang, Wang, Chen, Lieber, Charles M, Regev, Aviv, He, Zhigang, and Sanes, Joshua R

Subjects
Eye Disease and Disorders of Vision, Genetics, Physical Injury - Accidents and Adverse Effects, Neurodegenerative, Biotechnology, Regenerative Medicine, Neurosciences, 2.1 Biological and endogenous factors, Aetiology, Neurological, Eye, Animals, Cell Survival, Female, Male, Mice, Nerve Crush, Nerve Regeneration, Neuroprotection, Retinal Ganglion Cells, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Neuronal types in the central nervous system differ dramatically in their resilience to injury or other insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ∼80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC; characterized transcriptomic, physiological, and morphological changes that preceded degeneration; and identified genes selectively expressed by each type. Finally, using loss- and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.

Published
2019

6. Proper acquisition of cell class identity in organoids allows definition of fate specification programs of the human cerebral cortex

Author

Uzquiano, Ana, Kedaigle, Amanda J., Pigoni, Martina, Paulsen, Bruna, Adiconis, Xian, Kim, Kwanho, Faits, Tyler, Nagaraja, Surya, Antón-Bolaños, Noelia, Gerhardinger, Chiara, Tucewicz, Ashley, Murray, Evan, Jin, Xin, Buenrostro, Jason, Chen, Fei, Velasco, Silvia, Regev, Aviv, Levin, Joshua Z., and Arlotta, Paola

Published
2022
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10. Autism genes converge on asynchronous development of shared neuron classes

Author

Paulsen, Bruna, Velasco, Silvia, Kedaigle, Amanda J., Pigoni, Martina, Quadrato, Giorgia, Deo, Anthony J., Adiconis, Xian, Uzquiano, Ana, Sartore, Rafaela, Yang, Sung Min, Simmons, Sean K., Symvoulidis, Panagiotis, Kim, Kwanho, Tsafou, Kalliopi, Podury, Archana, Abbate, Catherine, Tucewicz, Ashley, Smith, Samantha N., Albanese, Alexandre, Barrett, Lindy, Sanjana, Neville E., Shi, Xi, Chung, Kwanghun, Lage, Kasper, Boyden, Edward S., Regev, Aviv, Levin, Joshua Z., and Arlotta, Paola

Published
2022
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13. Transcriptomic Characterization of SF3B1 Mutation Reveals Its Pleiotropic Effects in Chronic Lymphocytic Leukemia

Author

Wang, Lili, Brooks, Angela N, Fan, Jean, Wan, Youzhong, Gambe, Rutendo, Li, Shuqiang, Hergert, Sarah, Yin, Shanye, Freeman, Samuel S, Levin, Joshua Z, Fan, Lin, Seiler, Michael, Buonamici, Silvia, Smith, Peter G, Chau, Kevin F, Cibulskis, Carrie L, Zhang, Wandi, Rassenti, Laura Z, Ghia, Emanuela M, Kipps, Thomas J, Fernandes, Stacey, Bloch, Donald B, Kotliar, Dylan, Landau, Dan A, Shukla, Sachet A, Aster, Jon C, Reed, Robin, DeLuca, David S, Brown, Jennifer R, Neuberg, Donna, Getz, Gad, Livak, Kenneth J, Meyerson, Matthew M, Kharchenko, Peter V, and Wu, Catherine J

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Hematology, Lymphatic Research, Human Genome, Genetics, Rare Diseases, Cancer, Lymphoma, 2.1 Biological and endogenous factors, Alternative Splicing, Cell Line, Tumor, Dishevelled Proteins, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Phosphoproteins, RNA Splicing Factors, Receptors, Notch, Signal Transduction, CLL, Notch signaling, RNA sequencing, SF3B1, alternative splicing, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affected by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1. SF3B1 mutation was found to dysregulate multiple cellular functions including DNA damage response, telomere maintenance, and Notch signaling (mediated through KLF8 upregulation, increased TERC and TERT expression, or altered splicing of DVL2 transcript, respectively). SF3B1 mutation leads to diverse changes in CLL-related pathways.

Published
2016

14. Comprehensive Classification of Retinal Bipolar Neurons by Single-Cell Transcriptomics

Author

Shekhar, Karthik, Lapan, Sylvain W, Whitney, Irene E, Tran, Nicholas M, Macosko, Evan Z, Kowalczyk, Monika, Adiconis, Xian, Levin, Joshua Z, Nemesh, James, Goldman, Melissa, McCarroll, Steven A, Cepko, Constance L, Regev, Aviv, and Sanes, Joshua R

Subjects
Genetics, Neurosciences, Biotechnology, Underpinning research, 1.1 Normal biological development and functioning, Amacrine Cells, Animals, Cluster Analysis, Female, Genetic Markers, Male, Mice, Mice, Inbred Strains, Mice, Transgenic, Retinal Bipolar Cells, Sequence Analysis, RNA, Single-Cell Analysis, Transcription, Genetic, Transcriptome, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Patterns of gene expression can be used to characterize and classify neuronal types. It is challenging, however, to generate taxonomies that fulfill the essential criteria of being comprehensive, harmonizing with conventional classification schemes, and lacking superfluous subdivisions of genuine types. To address these challenges, we used massively parallel single-cell RNA profiling and optimized computational methods on a heterogeneous class of neurons, mouse retinal bipolar cells (BCs). From a population of ∼25,000 BCs, we derived a molecular classification that identified 15 types, including all types observed previously and two novel types, one of which has a non-canonical morphology and position. We validated the classification scheme and identified dozens of novel markers using methods that match molecular expression to cell morphology. This work provides a systematic methodology for achieving comprehensive molecular classification of neurons, identifies novel neuronal types, and uncovers transcriptional differences that distinguish types within a class.

Published
2016

15. Distinct subnetworks of the thalamic reticular nucleus

Author

Li, Yinqing, Lopez-Huerta, Violeta G., Adiconis, Xian, Levandowski, Kirsten, Choi, Soonwook, Simmons, Sean K., Arias-Garcia, Mario A., Guo, Baolin, Yao, Annie Y., Blosser, Timothy R., Wimmer, Ralf D., Aida, Tomomi, Atamian, Alexander, Naik, Tina, Sun, Xuyun, Bi, Dasheng, Malhotra, Diya, Hession, Cynthia C., Shema, Reut, Gomes, Marcos, Li, Taibo, Hwang, Eunjin, Krol, Alexandra, Kowalczyk, Monika, Peça, João, Pan, Gang, Halassa, Michael M., Levin, Joshua Z., Fu, Zhanyan, and Feng, Guoping

Published
2020
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16. Systematic comparison of single-cell and single-nucleus RNA-sequencing methods

Author

Ding, Jiarui, Adiconis, Xian, Simmons, Sean K., Kowalczyk, Monika S., Hession, Cynthia C., Marjanovic, Nemanja D., Hughes, Travis K., Wadsworth, Marc H., Burks, Tyler, Nguyen, Lan T., Kwon, John Y. H., Barak, Boaz, Ge, William, Kedaigle, Amanda J., Carroll, Shaina, Li, Shuqiang, Hacohen, Nir, Rozenblatt-Rosen, Orit, Shalek, Alex K., Villani, Alexandra-Chloé, Regev, Aviv, and Levin, Joshua Z.

Published
2020
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17. Benchmarking single-cell RNA-sequencing protocols for cell atlas projects

Author

Mereu, Elisabetta, Lafzi, Atefeh, Moutinho, Catia, Ziegenhain, Christoph, McCarthy, Davis J., Álvarez-Varela, Adrián, Batlle, Eduard, Sagar, Grün, Dominic, Lau, Julia K., Boutet, Stéphane C., Sanada, Chad, Ooi, Aik, Jones, Robert C., Kaihara, Kelly, Brampton, Chris, Talaga, Yasha, Sasagawa, Yohei, Tanaka, Kaori, Hayashi, Tetsutaro, Braeuning, Caroline, Fischer, Cornelius, Sauer, Sascha, Trefzer, Timo, Conrad, Christian, Adiconis, Xian, Nguyen, Lan T., Regev, Aviv, Levin, Joshua Z., Parekh, Swati, Janjic, Aleksandar, Wange, Lucas E., Bagnoli, Johannes W., Enard, Wolfgang, Gut, Marta, Sandberg, Rickard, Nikaido, Itoshi, Gut, Ivo, Stegle, Oliver, and Heyn, Holger

Published
2020
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24. Fetal brain response to maternal inflammation requires microglia.

Author

Ostrem, Bridget Elaine LaMonica, Domínguez-Iturza, Nuria, Stogsdill, Jeffrey A., Faits, Tyler, Kim, Kwanho, Levin, Joshua Z., and Arlotta, Paola

Subjects
FETAL brain, MATERNAL immune activation, MICROGLIA, EMBRYOLOGY, FETAL development, INFLAMMATION
Abstract

In utero infection and maternal inflammation can adversely impact fetal brain development. Maternal systemic illness, even in the absence of direct fetal brain infection, is associated with an increased risk of neuropsychiatric disorders in affected offspring. The cell types mediating the fetal brain response to maternal inflammation are largely unknown, hindering the development of novel treatment strategies. Here, we show that microglia, the resident phagocytes of the brain, highly express receptors for relevant pathogens and cytokines throughout embryonic development. Using a rodent maternal immune activation (MIA) model in which polyinosinic: polycytidylic acid is injected into pregnant mice, we demonstrate long-lasting transcriptional changes in fetal microglia that persist into postnatal life. We find that MIA induces widespread gene expression changes in neuronal and non-neuronal cells; importantly, these responses are abolished by selective genetic deletion of microglia, indicating that microglia are required for the transcriptional response of other cortical cell types to MIA. These findings demonstrate that microglia play a crucial durable role in the fetal response to maternal inflammation, and should be explored as potential therapeutic cell targets. [ABSTRACT FROM AUTHOR]

Published
2024
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25. Autism genes converge on asynchronous development of shared neuron classes

Author

Massachusetts Institute of Technology. Department of Biology, Paulsen, Bruna, Velasco, Silvia, Kedaigle, Amanda J, Pigoni, Martina, Quadrato, Giorgia, Deo, Anthony J, Adiconis, Xian, Uzquiano, Ana, Sartore, Rafaela, Yang, Sung Min, Simmons, Sean K, Symvoulidis, Panagiotis, Kim, Kwanho, Tsafou, Kalliopi, Podury, Archana, Abbate, Catherine, Tucewicz, Ashley, Smith, Samantha N, Albanese, Alexandre, Barrett, Lindy, Sanjana, Neville E, Shi, Xi, Chung, Kwanghun, Lage, Kasper, Boyden, Edward S, Regev, Aviv, Levin, Joshua Z, Arlotta, Paola, Massachusetts Institute of Technology. Department of Biology, Paulsen, Bruna, Velasco, Silvia, Kedaigle, Amanda J, Pigoni, Martina, Quadrato, Giorgia, Deo, Anthony J, Adiconis, Xian, Uzquiano, Ana, Sartore, Rafaela, Yang, Sung Min, Simmons, Sean K, Symvoulidis, Panagiotis, Kim, Kwanho, Tsafou, Kalliopi, Podury, Archana, Abbate, Catherine, Tucewicz, Ashley, Smith, Samantha N, Albanese, Alexandre, Barrett, Lindy, Sanjana, Neville E, Shi, Xi, Chung, Kwanghun, Lage, Kasper, Boyden, Edward S, Regev, Aviv, Levin, Joshua Z, and Arlotta, Paola

Published
2023

26. Mostly natural sequencing-by-synthesis for scRNA-seq using Ultima sequencing

Author

Massachusetts Institute of Technology. Department of Biology, Simmons, Sean K, Lithwick-Yanai, Gila, Adiconis, Xian, Oberstrass, Florian, Iremadze, Nika, Geiger-Schuller, Kathryn, Thakore, Pratiksha I, Frangieh, Chris J, Barad, Omer, Almogy, Gilad, Rozenblatt-Rosen, Orit, Regev, Aviv, Lipson, Doron, Levin, Joshua Z, Massachusetts Institute of Technology. Department of Biology, Simmons, Sean K, Lithwick-Yanai, Gila, Adiconis, Xian, Oberstrass, Florian, Iremadze, Nika, Geiger-Schuller, Kathryn, Thakore, Pratiksha I, Frangieh, Chris J, Barad, Omer, Almogy, Gilad, Rozenblatt-Rosen, Orit, Regev, Aviv, Lipson, Doron, and Levin, Joshua Z

Abstract

AbstractHere we introduce a mostly natural sequencing-by-synthesis (mnSBS) method for single-cell RNA sequencing (scRNA-seq), adapted to the Ultima genomics platform, and systematically benchmark it against current scRNA-seq technology. mnSBS uses mostly natural, unmodified nucleotides and only a low fraction of fluorescently labeled nucleotides, which allows for high polymerase processivity and lower costs. We demonstrate successful application in four scRNA-seq case studies of different technical and biological types, including 5′ and 3′ scRNA-seq, human peripheral blood mononuclear cells from a single individual and in multiplex, as well as Perturb-Seq. Benchmarking shows that results from mnSBS-based scRNA-seq are very similar to those using Illumina sequencing, with minor differences in results related to the position of reads relative to annotated gene boundaries, owing to single-end reads of Ultima being closer to gene ends than reads from Illumina. The method is thus compatible with state-of-the-art scRNA-seq libraries independent of the sequencing technology. We expect mnSBS to be of particular utility for cost-effective large-scale scRNA-seq projects.

Published
2023

27. The evolution, evolvability and engineering of gene regulatory DNA

Author

Massachusetts Institute of Technology. Department of Biology, Vaishnav, Eeshit Dhaval, de Boer, Carl G, Molinet, Jennifer, Yassour, Moran, Fan, Lin, Adiconis, Xian, Thompson, Dawn A, Levin, Joshua Z, Cubillos, Francisco A, Regev, Aviv, Massachusetts Institute of Technology. Department of Biology, Vaishnav, Eeshit Dhaval, de Boer, Carl G, Molinet, Jennifer, Yassour, Moran, Fan, Lin, Adiconis, Xian, Thompson, Dawn A, Levin, Joshua Z, Cubillos, Francisco A, and Regev, Aviv

Abstract

Mutations in non-coding regulatory DNA sequences can alter gene expression, organismal phenotype and fitness1-3. Constructing complete fitness landscapes, in which DNA sequences are mapped to fitness, is a long-standing goal in biology, but has remained elusive because it is challenging to generalize reliably to vast sequence spaces4-6. Here we build sequence-to-expression models that capture fitness landscapes and use them to decipher principles of regulatory evolution. Using millions of randomly sampled promoter DNA sequences and their measured expression levels in the yeast Saccharomyces cerevisiae, we learn deep neural network models that generalize with excellent prediction performance, and enable sequence design for expression engineering. Using our models, we study expression divergence under genetic drift and strong-selection weak-mutation regimes to find that regulatory evolution is rapid and subject to diminishing returns epistasis; that conflicting expression objectives in different environments constrain expression adaptation; and that stabilizing selection on gene expression leads to the moderation of regulatory complexity. We present an approach for using such models to detect signatures of selection on expression from natural variation in regulatory sequences and use it to discover an instance of convergent regulatory evolution. We assess mutational robustness, finding that regulatory mutation effect sizes follow a power law, characterize regulatory evolvability, visualize promoter fitness landscapes, discover evolvability archetypes and illustrate the mutational robustness of natural regulatory sequence populations. Our work provides a general framework for designing regulatory sequences and addressing fundamental questions in regulatory evolution.

Published
2023

28. Clinical Sequencing Uncovers Origins and Evolution of Lassa Virus

Author

Andersen, Kristian G., Shapiro, B. Jesse, Matranga, Christian B., Sealfon, Rachel, Lin, Aaron E., Moses, Lina M., Folarin, Onikepe A., Goba, Augustine, Odia, Ikponmwonsa, Ehiane, Philomena E., Momoh, Mambu, England, Eleina M., Winnicki, Sarah, Branco, Luis M., Gire, Stephen K., Phelan, Eric, Tariyal, Ridhi, Tewhey, Ryan, Omoniwa, Omowunmi, Fullah, Mohammed, Fonnie, Richard, Fonnie, Mbalu, Kanneh, Lansana, Jalloh, Simbirie, Gbakie, Michael, Saffa, Sidiki, Karbo, Kandeh, Gladden, Adrianne D., Qu, James, Stremlau, Matthew, Nekoui, Mahan, Finucane, Hilary K., Tabrizi, Shervin, Vitti, Joseph J., Birren, Bruce, Fitzgerald, Michael, McCowan, Caryn, Ireland, Andrea, Berlin, Aaron M., Bochicchio, James, Tazon-Vega, Barbara, Lennon, Niall J., Ryan, Elizabeth M., Bjornson, Zach, Milner, Danny A., Jr., Lukens, Amanda K., Broodie, Nisha, Rowland, Megan, Heinrich, Megan, Akdag, Marjan, Schieffelin, John S., Levy, Danielle, Akpan, Henry, Bausch, Daniel G., Rubins, Kathleen, McCormick, Joseph B., Lander, Eric S., Günther, Stephan, Hensley, Lisa, Okogbenin, Sylvanus, Schaffner, Stephen F., Okokhere, Peter O., Khan, S. Humarr, Grant, Donald S., Akpede, George O., Asogun, Danny A., Gnirke, Andreas, Levin, Joshua Z., Happi, Christian T., Garry, Robert F., and Sabeti, Pardis C.

Published
2015
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29. Author Correction: Systematic comparison of single-cell and single-nucleus RNA-sequencing methods

Author

Ding, Jiarui, Adiconis, Xian, Simmons, Sean K., Kowalczyk, Monika S., Hession, Cynthia C., Marjanovic, Nemanja D., Hughes, Travis K., Wadsworth, Marc H., Burks, Tyler, Nguyen, Lan T., Kwon, John Y. H., Barak, Boaz, Ge, William, Kedaigle, Amanda J., Carroll, Shaina, Li, Shuqiang, Hacohen, Nir, Rozenblatt-Rosen, Orit, Shalek, Alex K., Villani, Alexandra-Chloé, Regev, Aviv, and Levin, Joshua Z.

Published
2020
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32. Mostly natural sequencing-by-synthesis for scRNA-seq using Ultima sequencing

Author

Simmons, Sean K., primary, Lithwick-Yanai, Gila, additional, Adiconis, Xian, additional, Oberstrass, Florian, additional, Iremadze, Nika, additional, Geiger-Schuller, Kathryn, additional, Thakore, Pratiksha I., additional, Frangieh, Chris J., additional, Barad, Omer, additional, Almogy, Gilad, additional, Rozenblatt-Rosen, Orit, additional, Regev, Aviv, additional, Lipson, Doron, additional, and Levin, Joshua Z., additional

Published
2022
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33. Comparative Functional Genomics of the Fission Yeasts

Author

Rhind, Nicholas, Chen, Zehua, Yassour, Moran, Thompson, Dawn A., Haas, Brian J., Habib, Naomi, Wapinski, Ilan, Roy, Sushmita, Lin, Michael F., Heiman, David I., Young, Sarah K., Furuya, Kanji, Guo, Yabin, Pidoux, Alison, Chen, Huei Mei, Robbertse, Barbara, Goldberg, Jonathan M., Aoki, Keita, Bayne, Elizabeth H., Berlin, Aaron M., Desjardins, Christopher A., Dobbs, Edward, Dukaj, Livio, Fan, Lin, FitzGerald, Michael G., French, Courtney, Gujja, Sharvari, Hansen, Klavs, Keifenheim, Dan, Levin, Joshua Z., Mosher, Rebecca A., Müller, Carolin A., Pfiffner, Jenna, Priest, Margaret, Russ, Carsten, Smialowska, Agata, Swoboda, Peter, Sykes, Sean M., Vaughn, Matthew, Vengrova, Sonya, Yoder, Ryan, Zeng, Qiandong, Allshire, Robin, Baulcombe, David, Birren, Bruce W., Brown, William, Ekwall, Karl, Kellis, Manolis, Leatherwood, Janet, Levin, Henry, Margalit, Hanah, Martienssen, Rob, Nieduszynski, Conrad A., Spatafora, Joseph W., Friedman, Nir, Dalgaard, Jacob Z., Baumann, Peter, Niki, Hironori, Regev, Aviv, and Nusbaum, Chad

Published
2011
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35. In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes

Author

McGovern Institute for Brain Research at MIT, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology. Department of Biological Engineering, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Biology, Jin, Xin, Simmons, Sean K., Guo, Amy, Shetty, Ashwin S., Ko, Michelle, Nguyen, Lan, Jokhi, Vahbiz, Robinson, Elise, Oyler, Paul, Curry, Nathan, Deangeli, Giulio, Lodato, Simona, Levin, Joshua Z., Regev, Aviv, Zhang, Feng, Arlotta, Paola, McGovern Institute for Brain Research at MIT, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology. Department of Biological Engineering, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Biology, Jin, Xin, Simmons, Sean K., Guo, Amy, Shetty, Ashwin S., Ko, Michelle, Nguyen, Lan, Jokhi, Vahbiz, Robinson, Elise, Oyler, Paul, Curry, Nathan, Deangeli, Giulio, Lodato, Simona, Levin, Joshua Z., Regev, Aviv, Zhang, Feng, and Arlotta, Paola

Abstract

© 2020 American Association for the Advancement of Science. All rights reserved. The number of disease risk genes and loci identified through human genetic studies far outstrips the capacity to systematically study their functions. We applied a scalable genetic screening approach, in vivo Perturb-Seq, to functionally evaluate 35 autism spectrum disorder/neurodevelopmental delay (ASD/ND) de novo loss-of-function risk genes. Using CRISPR-Cas9, we introduced frameshift mutations in these risk genes in pools, within the developing mouse brain in utero, followed by single-cell RNAsequencing of perturbed cells in the postnatal brain. We identified cell type-specific and evolutionarily conserved gene modules from both neuronal and glial cell classes. Recurrent gene modules and cell types are affected across this cohort of perturbations, representing key cellular effects across sets of ASD/ND risk genes. In vivo Perturb-Seq allows us to investigate how diverse mutations affect cell types and states in the developing organism.

Published
2022

38. Single-cell transcriptomics reveals bimodality in expression and splicing in immune cells

Author

Shalek, Alex K., Satija, Rahul, Adiconis, Xian, Gertner, Rona S., Gaublomme, Jellert T., Raychowdhury, Raktima, Schwartz, Schraga, Yosef, Nir, Malboeuf, Christine, Lu, Diana, Trombetta, John J., Gennert, Dave, Gnirke, Andreas, Goren, Alon, Hacohen, Nir, Levin, Joshua Z., Park, Hongkun, and Regev, Aviv

Subjects
Physiological aspects, Genetic aspects, RNA splicing -- Physiological aspects, Immune system -- Genetic aspects, Gene expression -- Physiological aspects
Abstract

Author(s): Alex K. Shalek [sup.1] , Rahul Satija [sup.2] , Xian Adiconis [sup.2] , Rona S. Gertner [sup.1] , Jellert T. Gaublomme [sup.1] , Raktima Raychowdhury [sup.2] , Schraga Schwartz [...], Single-cell RNA sequencing is used to investigate the transcriptional response of 18 mouse bone-marrow-derived dendritic cells after lipopolysaccharide stimulation; many highly expressed genes, such as key immune genes and cytokines, show bimodal variation in both transcript abundance and splicing patterns. This variation reflects differences in both cell state and usage of an interferon-driven pathway involving Stat2 and Irf7. Heterogeneity in immune cells Gene expression profiles are typically derived at cell-population level, yet there is growing evidence to suggest that seemingly identical individual cells can differ considerably in their gene expression. This paper describes the use of single-cell RNA sequencing (RNA-Seq) to analyse the transcriptional response of 18 mouse bone-marrow-derived dendritic cells after lipopolysaccharide stimulation. The authors find that even genes that are highly expressed at the population level -- such as key immune genes and cytokines -- are often bimodally expressed. They may be very highly expressed in one cell, and expressed hardly at all in another. This variation reflects differences in both cell state and usage of an interferon-driven pathway involving Stat2 and Irf7. The SMART-Seq technology used here could have wide application in the study of regulatory circuits at the single-cell level. Recent molecular studies have shown that, even when derived from a seemingly homogenous population, individual cells can exhibit substantial differences in gene expression, protein levels and phenotypic output.sup.1,2,3,4,5, with important functional consequences.sup.4,5. Existing studies of cellular heterogeneity, however, have typically measured only a few pre-selected RNAs.sup.1,2 or proteins.sup.5,6 simultaneously, because genomic profiling methods.sup.3 could not be applied to single cells until very recently.sup.7,8,9,10. Here we use single-cell RNA sequencing to investigate heterogeneity in the response of mouse bone-marrow-derived dendritic cells (BMDCs) to lipopolysaccharide. We find extensive, and previously unobserved, bimodal variation in messenger RNA abundance and splicing patterns, which we validate by RNA-fluorescence in situ hybridization for select transcripts. In particular, hundreds of key immune genes are bimodally expressed across cells, surprisingly even for genes that are very highly expressed at the population average. Moreover, splicing patterns demonstrate previously unobserved levels of heterogeneity between cells. Some of the observed bimodality can be attributed to closely related, yet distinct, known maturity states of BMDCs; other portions reflect differences in the usage of key regulatory circuits. For example, we identify a module of 137 highly variable, yet co-regulated, antiviral response genes. Using cells from knockout mice, we show that variability in this module may be propagated through an interferon feedback circuit, involving the transcriptional regulators Stat2 and Irf7. Our study demonstrates the power and promise of single-cell genomics in uncovering functional diversity between cells and in deciphering cell states and circuits.

Published
2013
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39. Full-length transcriptome assembly from RNA-Seq data without a reference genome

Author

Grabherr, Manfred G, Haas, Brian J, Yassour, Moran, Levin, Joshua Z, Thompson, Dawn A, Amit, Ido, Adiconis, Xian, Fan, Lin, Raychowdhury, Raktima, Zeng, Qiandong, Chen, Zehua, Mauceli, Evan, Hacohen, Nir, Gnirke, Andreas, Rhind, Nicholas, di Palma, Federica, Birren, Bruce W, Nusbaum, Chad, Lindblad-Toh, Kerstin, Friedman, Nir, and Regev, Aviv

Published
2011
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40. Additional file 1 of Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity

Author

Sorek, Matan, Walaa Oweis, Nissim-Rafinia, Malka, Moria Maman, Simon, Shahar, Hession, Cynthia C., Adiconis, Xian, Simmons, Sean K., Sanjana, Neville E., Shi, Xi, Congyi Lu, Pan, Jen Q., Xiaohong Xu, Pouladi, Mahmoud A., Ellerby, Lisa M., Zhang, Feng, Levin, Joshua Z., and Meshorer, Eran

Abstract

Additional file 1: Supplementary Figures and Figure legends S1-S6 and Supplementary Methods.

Published
2021
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41. Additional file 6 of Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity

Author

Sorek, Matan, Walaa Oweis, Nissim-Rafinia, Malka, Moria Maman, Simon, Shahar, Hession, Cynthia C., Adiconis, Xian, Simmons, Sean K., Sanjana, Neville E., Shi, Xi, Congyi Lu, Pan, Jen Q., Xiaohong Xu, Pouladi, Mahmoud A., Ellerby, Lisa M., Zhang, Feng, Levin, Joshua Z., and Meshorer, Eran

Abstract

Additional file 6. Review history.

Published
2021
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42. In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes

Author

Jin, Xin, Simmons, Sean K, Guo, Amy, Shetty, Ashwin S, Ko, Michelle, Nguyen, Lan, Jokhi, Vahbiz, Robinson, Elise, Oyler, Paul, Curry, Nathan, Deangeli, Giulio, Lodato, Simona, Levin, Joshua Z, Regev, Aviv, Zhang, Feng, Arlotta, Paola, Jin, Xin, Simmons, Sean K, Guo, Amy, Shetty, Ashwin S, Ko, Michelle, Nguyen, Lan, Jokhi, Vahbiz, Robinson, Elise, Oyler, Paul, Curry, Nathan, Deangeli, Giulio, Lodato, Simona, Levin, Joshua Z, Regev, Aviv, Zhang, Feng, and Arlotta, Paola

Abstract

© 2020 American Association for the Advancement of Science. All rights reserved. The number of disease risk genes and loci identified through human genetic studies far outstrips the capacity to systematically study their functions. We applied a scalable genetic screening approach, in vivo Perturb-Seq, to functionally evaluate 35 autism spectrum disorder/neurodevelopmental delay (ASD/ND) de novo loss-of-function risk genes. Using CRISPR-Cas9, we introduced frameshift mutations in these risk genes in pools, within the developing mouse brain in utero, followed by single-cell RNAsequencing of perturbed cells in the postnatal brain. We identified cell type-specific and evolutionarily conserved gene modules from both neuronal and glial cell classes. Recurrent gene modules and cell types are affected across this cohort of perturbations, representing key cellular effects across sets of ASD/ND risk genes. In vivo Perturb-Seq allows us to investigate how diverse mutations affect cell types and states in the developing organism.

Published
2021

43. Single-Cell Profiles of Retinal Ganglion Cells Differing in Resilience to Injury Reveal Neuroprotective Genes

Author

Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Tran, Nicholas M, Shekhar, Karthik, Whitney, Irene E, Jacobi, Anne, Benhar, Inbal, Hong, Guosong, Yan, Wenjun, Adiconis, Xian, Arnold, McKinzie E, Lee, Jung Min, Levin, Joshua Z, Lin, Dingchang, Wang, Chen, Lieber, Charles M, Regev, Aviv, He, Zhigang, Sanes, Joshua R, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Tran, Nicholas M, Shekhar, Karthik, Whitney, Irene E, Jacobi, Anne, Benhar, Inbal, Hong, Guosong, Yan, Wenjun, Adiconis, Xian, Arnold, McKinzie E, Lee, Jung Min, Levin, Joshua Z, Lin, Dingchang, Wang, Chen, Lieber, Charles M, Regev, Aviv, He, Zhigang, and Sanes, Joshua R

Abstract

© 2019 Elsevier Inc. Neuronal types in the central nervous system differ dramatically in their resilience to injury or other insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ∼80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC; characterized transcriptomic, physiological, and morphological changes that preceded degeneration; and identified genes selectively expressed by each type. Finally, using loss- and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.

Published
2021

44. Distinct subnetworks of the thalamic reticular nucleus

Author

McGovern Institute for Brain Research at MIT, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Klarman Cell Observatory (Broad Institute), Li, Yinqing, Lopez Huerta, Violeta, Adiconis, Xian, Levandowski, Kirsten, Choi, Soonwook, Simmons, Sean K., Arias-Garcia, Mario A., Guo, Baolin, Yao, Annie, Blosser, Timothy R., Wimmer, Ralf D, Aida, Tomomi, Atamian, Alexander, Naik, Tina, Sun, Xuyun, Bi, Dasheng, Malhotra, Diya, Hession, Cynthia C., Shema Tirosh, Reut, Gomes, Marcos, Li, Taibo, Hwang, Eunjin, Krol, Alexandra, Kowalczyk, Monika, Peça, João, Pan, Gang, Halassa, Michael, Levin, Joshua Z., Fu, Zhanyan, Feng, Guoping, McGovern Institute for Brain Research at MIT, Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, Klarman Cell Observatory (Broad Institute), Li, Yinqing, Lopez Huerta, Violeta, Adiconis, Xian, Levandowski, Kirsten, Choi, Soonwook, Simmons, Sean K., Arias-Garcia, Mario A., Guo, Baolin, Yao, Annie, Blosser, Timothy R., Wimmer, Ralf D, Aida, Tomomi, Atamian, Alexander, Naik, Tina, Sun, Xuyun, Bi, Dasheng, Malhotra, Diya, Hession, Cynthia C., Shema Tirosh, Reut, Gomes, Marcos, Li, Taibo, Hwang, Eunjin, Krol, Alexandra, Kowalczyk, Monika, Peça, João, Pan, Gang, Halassa, Michael, Levin, Joshua Z., Fu, Zhanyan, and Feng, Guoping

Abstract

The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, regulates thalamocortical interactions that are critical for sensory processing, attention and cognition1–5. TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders6–9. However, little is known about the organizational principles that underlie its divergent functions. Here we performed an integrative study linking single-cell molecular and electrophysiological features of the mouse TRN to connectivity and systems-level function. We found that cellular heterogeneity in the TRN is characterized by a transcriptomic gradient of two negatively correlated gene-expression profiles, each containing hundreds of genes. Neurons in the extremes of this transcriptomic gradient express mutually exclusive markers, exhibit core or shell-like anatomical structure and have distinct electrophysiological properties. The two TRN subpopulations make differential connections with the functionally distinct first-order and higher-order thalamic nuclei to form molecularly defined TRN–thalamus subnetworks. Selective perturbation of the two subnetworks in vivo revealed their differential role in regulating sleep. In sum, our study provides a comprehensive atlas of TRN neurons at single-cell resolution and links molecularly defined subnetworks to the functional organization of thalamocortical circuits., NIH/NIMH (Grants R01NS098505, R01NS113245), NIH (Grants R01NS098505, R01MH107680)

Published
2021

46. Arabidopsis hapless mutations define essential gametophytic functions

Author

Johnson, Mark A., von Besser, Kiera, Zhou, Qing, Smith, Evadne, Aux, George, Patton, David, Levin, Joshua Z., and Preuss, Dapne

Subjects
Phanerogams -- Genetic aspects, Gametophyte -- Genetic aspects, Arabidopsis -- Genetic aspects, Plant mutation, Genetic research, Gene mutations, Biological sciences
Abstract

In flowering plants, the egg develops within a haploid embryo sac (female gametophyte) that is encased within the pistil. The haploid pollen grain (male gametophyte) extends a pollen tube that carries two sperm cells within its cytoplasm to the embryo sac. This feat requires rapid, precisely guided, and highly polarized growth through, between, and on the surface of the cells of the stigma, style, and ovary. Pollen tribe migration depends on a series of long-range signals from diploid female cells as well as a short-range attractant emitted by the embryo sac that guides the final stage of tube growth. We developed a genetic screen in Arabidopsis thaliana that tags mutant pollen with a cell-autonomous marker carried on an insertion element. We found 32 haploid-disrupting (hapless) mutations that define genes required for pollen grain development, pollen tube growth in the stigma and style, or pollen tube growth and guidance in the ovary. We also identified genomic DNA flanking the insertion element for eleven hap mutants and showed that hap1 disrupts AtMago, a gene whose ortholog is important for Drosophila cell polarity.

Published
2004

47. The African coelacanth genome provides insights into tetrapod evolution

Author

Amemiya, Chris T., Alföldi, Jessica J, Lee, Alison P., Fan, Shaohua S, Philippe, Hervé H, MacCallum, Iain I, Braasch, Ingo I, Manousaki, Tereza T, Schneider, Igor I, Rohner, Nicolas N, Organ, Chris C, Chalopin, Domitille D, Smith, Jeramiah J., Robinson, Mark M, Dorrington, Rosemary A., Gerdol, Marco M, Aken, Bronwen B, Biscotti, Maria Assunta, Barucca, Marco M, Baurain, Denis D, Berlin, Aaron M., Blatch, Gregory L., Buonocore, Francesco F, Burmester, Thorsten T, Campbell, Michael S., Canapa, Adriana A, Cannon, John P., Christoffels, Alan A, De Moro, Gianluca G, Edkins, Adrienne L., Fan, Lin L, Fausto, Anna Maria, Feiner, Nathalie N, Forconi, Mariko M, Gamieldien, Junaid J, Gnerre, Sante S, Gnirke, Andreas A, Goldstone, Jared V., Haerty, Wilfried W, Hahn, Mark E., Hesse, Uljana U, Hoffmann, Steve S, Johnson, Jeremy J, Karchner, Sibel I., Kuraku, Shigehiro S, Lara, Marcia M, Levin, Joshua Z., Litman, Gary W., Mauceli, Evan E, Miyake, Tsutomu T, Mueller, Gail M., Nelson, David R., Nitsche, Anne A, Olmo, Ettore E, Ota, Tatsuya T, Pallavicini, Alberto A, Panji, Sumir S, Picone, Barbara B, Ponting, Chris P., Prohaska, Sonja J., Przybylski, Dariusz D, Saha, Nil Ratan, Ravi, Vydianathan V, Ribeiro, Filipe J., Sauka-Spengler, Tatjana T, Scapigliati, Giuseppe G, Searle, Stephen M. J., Sharpe, Ted T, Simakov, Oleg O, Stadler, Peter F., Stegeman, John J., Sumiyama, Kenta K, Tabbaa, Diana D, Tafer, Hakim H, Turner-Maier, Jason J, van Heusden, Peter P, White, Simon S, Williams, Louise L, Yandell, Mark M, Brinkmann, Henner H, Volff, Jean-Nicolas J, Tabin, Clifford J., Shubin, Neil N, Schartl, Manfred M, Jaffe, David B., Postlethwait, John H., Venkatesh, Byrappa B, Di Palma, Federica F, Lander, Eric S., Meyer, Axel A, and Lindblad-Toh, Kerstin K

Published
2013
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48. Knock-out of the genes coding for the Rieske protein and the ATP-synthase [delta]-subunit of Arabidopsis. Effects on photosynthesis, thylakoid protein composition, and nuclear chloroplast gene expression (1) ([w])

Author

Maiwald, Daniela, Dietzmann, Angela, Jahns, Peter, Pesaresi, Paolo, Joliot, Pierre, Joliot, Anne, Levin, Joshua Z., Salamini, Francesco, and Leister, Dario

Subjects
Arabidopsis -- Genetic aspects, Oxidation-reduction reaction -- Analysis, Nucleic acids -- Separation, Nucleic acids -- Usage, Photosynthesis research, Biological sciences, Science and technology
Published
2003

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