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3. FOXO1 is a master regulator of memory programming in CAR T cells

Author

Doan, Alexander E., Mueller, Katherine P., Chen, Andy Y., Rouin, Geoffrey T., Chen, Yingshi, Daniel, Bence, Lattin, John, Markovska, Martina, Mozarsky, Brett, Arias-Umana, Jose, Hapke, Robert, Jung, In-Young, Wang, Alice, Xu, Peng, Klysz, Dorota, Zuern, Gabrielle, Bashti, Malek, Quinn, Patrick J., Miao, Zhuang, Sandor, Katalin, Zhang, Wenxi, Chen, Gregory M., Ryu, Faith, Logun, Meghan, Hall, Junior, Tan, Kai, Grupp, Stephan A., McClory, Susan E., Lareau, Caleb A., Fraietta, Joseph A., Sotillo, Elena, Satpathy, Ansuman T., Mackall, Crystal L., and Weber, Evan W.

Published
2024
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4. Mitochondrial single-cell ATAC-seq for high-throughput multi-omic detection of mitochondrial genotypes and chromatin accessibility.

Author

Lareau, Caleb, Liu, Vincent, Muus, Christoph, Praktiknjo, Samantha, Nitsch, Lena, Kautz, Pauline, Sandor, Katalin, Yin, Yajie, Gutierrez, Jacob, Pelka, Karin, Satpathy, Ansuman, Regev, Aviv, Sankaran, Vijay, and Ludwig, Leif

Subjects
Animals, Humans, Chromatin, Chromatin Immunoprecipitation Sequencing, Multiomics, Sequence Analysis, DNA, High-Throughput Nucleotide Sequencing, DNA, Mitochondrial, Genotype, Mammals
Abstract

Natural sequence variation within mitochondrial DNA (mtDNA) contributes to human phenotypes and may serve as natural genetic markers in human cells for clonal and lineage tracing. We recently developed a single-cell multi-omic approach, called mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (mtscATAC-seq), enabling concomitant high-throughput mtDNA genotyping and accessible chromatin profiling. Specifically, our technique allows the mitochondrial genome-wide inference of mtDNA variant heteroplasmy along with information on cell state and accessible chromatin variation in individual cells. Leveraging somatic mtDNA mutations, our method further enables inference of clonal relationships among native ex vivo-derived human cells not amenable to genetic engineering-based clonal tracing approaches. Here, we provide a step-by-step protocol for the use of mtscATAC-seq, including various cell-processing and flow cytometry workflows, by using primary hematopoietic cells, subsequent single-cell genomic library preparation and sequencing that collectively take ~3-4 days to complete. We discuss experimental and computational data quality control metrics and considerations for the extension to other mammalian tissues. Overall, mtscATAC-seq provides a broadly applicable platform to map clonal relationships between cells in human tissues, investigate fundamental aspects of mitochondrial genetics and enable additional modes of multi-omic discovery.

Published
2023

5. A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation

Author

Kedmi, Ranit, Najar, Tariq A, Mesa, Kailin R, Grayson, Allyssa, Kroehling, Lina, Hao, Yuhan, Hao, Stephanie, Pokrovskii, Maria, Xu, Mo, Talbot, Jhimmy, Wang, Jiaxi, Germino, Joe, Lareau, Caleb A, Satpathy, Ansuman T, Anderson, Mark S, Laufer, Terri M, Aifantis, Iannis, Bartleson, Juliet M, Allen, Paul M, Paidassi, Helena, Gardner, James M, Stoeckius, Marlon, and Littman, Dan R

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Microbiology, Immunology, Autoimmune Disease, Emerging Infectious Diseases, Digestive Diseases, Infectious Diseases, Vaccine Related, Prevention, Biodefense, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, Inflammatory and immune system, Oral and gastrointestinal, Cell Differentiation, Dendritic Cells, Gastrointestinal Microbiome, Homeostasis, Immunity, Innate, Integrin alphaV, Nuclear Receptor Subfamily 1, Group F, Member 3, Receptors, CCR7, T-Lymphocytes, Regulatory, Th17 Cells, Transforming Growth Factor beta, Antigen Presentation, Antigen-Presenting Cells, General Science & Technology
Abstract

The mutualistic relationship of gut-resident microbiota and the host immune system promotes homeostasis that ensures maintenance of the microbial community and of a largely non-aggressive immune cell compartment1,2. The consequences of disturbing this balance include proximal inflammatory conditions, such as Crohn's disease, and systemic illnesses. This equilibrium is achieved in part through the induction of both effector and suppressor arms of the adaptive immune system. Helicobacter species induce T regulatory (Treg) and T follicular helper (TFH) cells under homeostatic conditions, but induce inflammatory T helper 17 (TH17) cells when induced Treg (iTreg) cells are compromised3,4. How Helicobacter and other gut bacteria direct T cells to adopt distinct functions remains poorly understood. Here we investigated the cells and molecular components required for iTreg cell differentiation. We found that antigen presentation by cells expressing RORγt, rather than by classical dendritic cells, was required and sufficient for induction of Treg cells. These RORγt+ cells-probably type 3 innate lymphoid cells and/or Janus cells5-require the antigen-presentation machinery, the chemokine receptor CCR7 and the TGFβ activator αv integrin. In the absence of any of these factors, there was expansion of pathogenic TH17 cells instead of iTreg cells, induced by CCR7-independent antigen-presenting cells. Thus, intestinal commensal microbes and their products target multiple antigen-presenting cells with pre-determined features suited to directing appropriate T cell differentiation programmes, rather than a common antigen-presenting cell that they endow with appropriate functions.

Published
2022

6. Advancing T cell–based cancer therapy with single-cell technologies

Author

Bucktrout, Samantha L, Banovich, Nicholas E, Butterfield, Lisa H, Cimen-Bozkus, Cansu, Giles, Josephine R, Good, Zinaida, Goodman, Daniel, Jonsson, Vanessa D, Lareau, Caleb, Marson, Alexander, Maurer, Denna M, Munson, Paul V, Stubbington, Mike, Taylor, Sarah, and Cutchin, Abbey

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Vaccine Related, Rare Diseases, Orphan Drug, Biotechnology, Cancer, Immunization, Humans, Neoplasms, T-Lymphocytes, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Published
2022

7. Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency

Author

Obers, Andreas, Poch, Tobias, Rodrigues, Grace, Christo, Susan N., Gandolfo, Luke C., Fonseca, Raissa, Zaid, Ali, Kuai, Joey En Yu, Lai, Hongjin, Zareie, Pirooz, Yakou, Marina H., Dryburgh, Lachlan, Burn, Thomas N., Dosser, James, Buquicchio, Frank A., Lareau, Caleb A., Walsh, Calum, Judd, Louise, Theodorou, Maria Rafailia, Gutbrod, Katharina, Dörmann, Peter, Kingham, Jenny, Stinear, Tim, Kallies, Axel, Schroeder, Jan, Mueller, Scott N., Park, Simone L., Speed, Terence P., Satpathy, Ansuman T., Phan, Tri Giang, Wilhelm, Christoph, Zaph, Colby, Evrard, Maximilien, and Mackay, Laura K.

Published
2024
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10. Latent human herpesvirus 6 is reactivated in CAR T cells

Author

Lareau, Caleb A., Yin, Yajie, Maurer, Katie, Sandor, Katalin D., Daniel, Bence, Yagnik, Garima, Peña, José, Crawford, Jeremy Chase, Spanjaart, Anne M., Gutierrez, Jacob C., Haradhvala, Nicholas J., Riberdy, Janice M., Abay, Tsion, Stickels, Robert R., Verboon, Jeffrey M., Liu, Vincent, Buquicchio, Frank A., Wang, Fangyi, Southard, Jackson, Song, Ren, Li, Wenjing, Shrestha, Aastha, Parida, Laxmi, Getz, Gad, Maus, Marcela V., Li, Shuqiang, Moore, Alison, Roberts, Zachary J., Ludwig, Leif S., Talleur, Aimee C., Thomas, Paul G., Dehghani, Houman, Pertel, Thomas, Kundaje, Anshul, Gottschalk, Stephen, Roth, Theodore L., Kersten, Marie J., Wu, Catherine J., Majzner, Robbie G., and Satpathy, Ansuman T.

Published
2023
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11. Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History

Author

Penter, Livius, Gohil, Satyen H, Lareau, Caleb, Ludwig, Leif S, Parry, Erin M, Huang, Teddy, Li, Shuqiang, Zhang, Wandi, Livitz, Dimitri, Leshchiner, Ignaty, Parida, Laxmi, Getz, Gad, Rassenti, Laura Z, Kipps, Thomas J, Brown, Jennifer R, Davids, Matthew S, Neuberg, Donna S, Livak, Kenneth J, Sankaran, Vijay G, and Wu, Catherine J

Subjects
Clinical Research, Hematology, Human Genome, Cancer, Lymphoma, Rare Diseases, Genetics, 2.1 Biological and endogenous factors, Aetiology, Good Health and Well Being, Chromatin, Clonal Evolution, Clone Cells, DNA Copy Number Variations, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Mutation, Oncology and Carcinogenesis
Abstract

While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease course and utilize mitochondrial DNA (mtDNA) mutations as natural genetic markers of cancer clones. We observe stable propagation of mtDNA mutations over years in the absence of strong selective pressure, indicating clonal persistence, but dramatic changes following tight bottlenecks, including disease transformation and relapse posttherapy, paralleled by acquisition of copy-number variants and changes in chromatin accessibility and gene expression. Furthermore, we link CLL subclones to distinct chromatin states, providing insight into nongenetic sources of relapse. mtDNA mutations thus mirror disease history and provide naturally occurring genetic barcodes to enable patient-specific study of cancer subclonal dynamics.SignificanceSingle-cell multi-omic profiling of CLL reveals the utility of somatic mtDNA mutations as in vivo barcodes, which mark subclones that can evolve over time along with changes in accessible chromatin and gene expression profiles to capture dynamics of disease evolution. See related commentary by Hilton and Scott, p. 2965. This article is highlighted in the In This Issue feature, p. 2945.

Published
2021

12. A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification

Author

Liu, Chunhong, Nagashima, Hiroyuki, Fernando, Nilisha, Bass, Victor, Gopalakrishnan, Jaanam, Signorella, Sadie, Montgomery, Will, Lim, Ai Ing, Harrison, Oliver, Reich, Lauren, Yao, Chen, Sun, Hong-Wei, Brooks, Stephen R., Jiang, Kan, Nagarajan, Vijayaraj, Zhao, Yongbing, Jung, Seolkyoung, Philips, Rachael, Mikami, Yohei, Lareau, Caleb A., Kanno, Yuka, Jankovic, Dragana, Aryee, Martin J., Pękowska, Aleksandra, Belkaid, Yasmine, O’Shea, John, and Shih, Han-Yu

Published
2024
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13. Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells

Author

Lareau, Caleb A., Dubois, Sonia M., Buquicchio, Frank A., Hsieh, Yu-Hsin, Garg, Kopal, Kautz, Pauline, Nitsch, Lena, Praktiknjo, Samantha D., Maschmeyer, Patrick, Verboon, Jeffrey M., Gutierrez, Jacob C., Yin, Yajie, Fiskin, Evgenij, Luo, Wendy, Mimitou, Eleni P., Muus, Christoph, Malhotra, Rhea, Parikh, Sumit, Fleming, Mark D., Oevermann, Lena, Schulte, Johannes, Eckert, Cornelia, Kundaje, Anshul, Smibert, Peter, Vardhana, Santosha A., Satpathy, Ansuman T., Regev, Aviv, Sankaran, Vijay G., Agarwal, Suneet, and Ludwig, Leif S.

Published
2023
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14. Single-cell multiomics defines tolerogenic extrathymic Aire-expressing populations with unique homology to thymic epithelium

Author

Wang, Jiaxi, Lareau, Caleb A, Bautista, Jhoanne L, Gupta, Alexander R, Sandor, Katalin, Germino, Joe, Yin, Yajie, Arvedson, Matthew P, Reeder, Gabriella C, Cramer, Nathan T, Xie, Fang, Ntranos, Vasilis, Satpathy, Ansuman T, Anderson, Mark S, and Gardner, James M

Subjects
Autoimmune Disease, Human Genome, Genetics, Aetiology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Underpinning research, Inflammatory and immune system, Animals, Epithelium, Immune Tolerance, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Transgenic, Single-Cell Analysis, Thymus Gland, Transcription Factors
Abstract

The autoimmune regulator (Aire), a well-defined transcriptional regulator in the thymus, is also found in extrathymic Aire-expressing cells (eTACs) in the secondary lymphoid organs. eTACs are hematopoietic antigen-presenting cells and inducers of immune tolerance, but their precise identity has remained unclear. Here, we use single-cell multiomics, transgenic murine models, and functional approaches to define eTACs at the transcriptional, genomic, and proteomic level. We find that eTACs consist of two similar cell types: CCR7+ Aire-expressing migratory dendritic cells (AmDCs) and an Airehi population coexpressing Aire and retinoic acid receptor–related orphan receptor γt (RORγt) that we term Janus cells (JCs). Both JCs and AmDCs have the highest transcriptional and genomic homology to CCR7+ migratory dendritic cells. eTACs, particularly JCs, have highly accessible chromatin and broad gene expression, including a range of tissue-specific antigens, as well as remarkable homology to medullary thymic epithelium and RANK-dependent Aire expression. Transgenic self-antigen expression by eTACs is sufficient to induce negative selection and prevent autoimmune diabetes. This transcriptional, genomic, and functional symmetry between eTACs (both JCs and AmDCs) and medullary thymic epithelium—the other principal Aire-expressing population and a key regulator of central tolerance—identifies a core program that may influence self-representation and tolerance across the spectrum of immune development.

Published
2021

15. Integrated single-cell transcriptomics and epigenomics reveals strong germinal center–associated etiology of autoimmune risk loci

Author

King, Hamish W, Wells, Kristen L, Shipony, Zohar, Kathiria, Arwa S, Wagar, Lisa E, Lareau, Caleb, Orban, Nara, Capasso, Robson, Davis, Mark M, Steinmetz, Lars M, James, Louisa K, and Greenleaf, William J

Subjects
Autoimmune Disease, Genetics, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Autoimmunity, Cell Differentiation, Epigenomics, Germinal Center, Homeodomain Proteins, Humans, Interleukins, Palatine Tonsil, Sequence Analysis, RNA, Single-Cell Analysis, Trans-Activators, Transcription Factors, Transcriptome
Abstract

The germinal center (GC) response is critical for both effective adaptive immunity and establishing peripheral tolerance by limiting autoreactive B cells. Dysfunction in these processes can lead to defective immune responses to infection or contribute to autoimmune disease. To understand the gene regulatory principles underlying the GC response, we generated a single-cell transcriptomic and epigenomic atlas of the human tonsil, a widely studied and representative lymphoid tissue. We characterize diverse immune cell subsets and build a trajectory of dynamic gene expression and transcription factor activity during B cell activation, GC formation, and plasma cell differentiation. We subsequently leverage cell type–specific transcriptomic and epigenomic maps to interpret potential regulatory impact of genetic variants implicated in autoimmunity, revealing that many exhibit their greatest regulatory potential in GC-associated cellular populations. These included gene loci linked with known roles in GC biology (IL21, IL21R, IL4R, and BCL6) and transcription factors regulating B cell differentiation (POU2AF1 and HHEX). Together, these analyses provide a powerful new cell type–resolved resource for the interpretation of cellular and genetic causes underpinning autoimmune disease.

Published
2021

16. Publisher Correction: FOXO1 is a master regulator of memory programming in CAR T cells

Author

Doan, Alexander E., Mueller, Katherine P., Chen, Andy Y., Rouin, Geoffrey T., Chen, Yingshi, Daniel, Bence, Lattin, John, Markovska, Martina, Mozarsky, Brett, Arias-Umana, Jose, Hapke, Robert, Jung, In-Young, Wang, Alice, Xu, Peng, Klysz, Dorota, Zuern, Gabrielle, Bashti, Malek, Quinn, Patrick J., Miao, Zhuang, Sandor, Katalin, Zhang, Wenxi, Chen, Gregory M., Ryu, Faith, Logun, Meghan, Hall, Junior, Tan, Kai, Grupp, Stephan A., McClory, Susan E., Lareau, Caleb A., Fraietta, Joseph A., Sotillo, Elena, Satpathy, Ansuman T., Mackall, Crystal L., and Weber, Evan W.

Published
2024
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18. Co-opting signalling molecules enables logic-gated control of CAR T cells

Author

Tousley, Aidan M., Rotiroti, Maria Caterina, Labanieh, Louai, Rysavy, Lea Wenting, Kim, Won-Ju, Lareau, Caleb, Sotillo, Elena, Weber, Evan W., Rietberg, Skyler P., Dalton, Guillermo Nicolas, Yin, Yajie, Klysz, Dorota, Xu, Peng, de la Serna, Eva L., Dunn, Alexander R., Satpathy, Ansuman T., Mackall, Crystal L., and Majzner, Robbie G.

Published
2023
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20. SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9

Author

Schmidt, Nora, Ganskih, Sabina, Wei, Yuanjie, Gabel, Alexander, Zielinski, Sebastian, Keshishian, Hasmik, Lareau, Caleb A., Zimmermann, Liv, Makroczyova, Jana, Pearce, Cadence, Krey, Karsten, Hennig, Thomas, Stegmaier, Sebastian, Moyon, Lambert, Horlacher, Marc, Werner, Simone, Aydin, Jens, Olguin-Nava, Marco, Potabattula, Ramya, Kibe, Anuja, Dölken, Lars, Smyth, Redmond P., Caliskan, Neva, Marsico, Annalisa, Krempl, Christine, Bodem, Jochen, Pichlmair, Andreas, Carr, Steven A., Chlanda, Petr, Erhard, Florian, and Munschauer, Mathias

Published
2023
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21. Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations

Author

Chen, Ming-Huei, Raffield, Laura M, Mousas, Abdou, Sakaue, Saori, Huffman, Jennifer E, Moscati, Arden, Trivedi, Bhavi, Jiang, Tao, Akbari, Parsa, Vuckovic, Dragana, Bao, Erik L, Zhong, Xue, Manansala, Regina, Laplante, Véronique, Chen, Minhui, Lo, Ken Sin, Qian, Huijun, Lareau, Caleb A, Beaudoin, Mélissa, Hunt, Karen A, Akiyama, Masato, Bartz, Traci M, Ben-Shlomo, Yoav, Beswick, Andrew, Bork-Jensen, Jette, Bottinger, Erwin P, Brody, Jennifer A, van Rooij, Frank JA, Chitrala, Kumaraswamynaidu, Cho, Kelly, Choquet, Hélène, Correa, Adolfo, Danesh, John, Di Angelantonio, Emanuele, Dimou, Niki, Ding, Jingzhong, Elliott, Paul, Esko, Tõnu, Evans, Michele K, Floyd, James S, Broer, Linda, Grarup, Niels, Guo, Michael H, Greinacher, Andreas, Haessler, Jeff, Hansen, Torben, Howson, Joanna MM, Huang, Qin Qin, Huang, Wei, Jorgenson, Eric, Kacprowski, Tim, Kähönen, Mika, Kamatani, Yoichiro, Kanai, Masahiro, Karthikeyan, Savita, Koskeridis, Fotis, Lange, Leslie A, Lehtimäki, Terho, Lerch, Markus M, Linneberg, Allan, Liu, Yongmei, Lyytikäinen, Leo-Pekka, Manichaikul, Ani, Martin, Hilary C, Matsuda, Koichi, Mohlke, Karen L, Mononen, Nina, Murakami, Yoshinori, Nadkarni, Girish N, Nauck, Matthias, Nikus, Kjell, Ouwehand, Willem H, Pankratz, Nathan, Pedersen, Oluf, Preuss, Michael, Psaty, Bruce M, Raitakari, Olli T, Roberts, David J, Rich, Stephen S, Rodriguez, Benjamin AT, Rosen, Jonathan D, Rotter, Jerome I, Schubert, Petra, Spracklen, Cassandra N, Surendran, Praveen, Tang, Hua, Tardif, Jean-Claude, Trembath, Richard C, Ghanbari, Mohsen, Völker, Uwe, Völzke, Henry, Watkins, Nicholas A, Zonderman, Alan B, Program, VA Million Veteran, Wilson, Peter WF, Li, Yun, Butterworth, Adam S, Gauchat, Jean-François, Chiang, Charleston WK, and Li, Bingshan

Subjects
Genetics, Good Health and Well Being, Asian People, Genome-Wide Association Study, HEK293 Cells, Humans, Interleukin-7, Mutation, Missense, Phenotype, Polymorphism, Single Nucleotide, White People, VA Million Veteran Program, interleukin-7, genetic architecture, fine-mapping, selective sweeps, polygenic trait score, phenome-wide association study, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Most loci identified by GWASs have been found in populations of European ancestry (EUR). In trans-ethnic meta-analyses for 15 hematological traits in 746,667 participants, including 184,535 non-EUR individuals, we identified 5,552 trait-variant associations at p < 5 × 10-9, including 71 novel associations not found in EUR populations. We also identified 28 additional novel variants in ancestry-specific, non-EUR meta-analyses, including an IL7 missense variant in South Asians associated with lymphocyte count in vivo and IL-7 secretion levels in vitro. Fine-mapping prioritized variants annotated as functional and generated 95% credible sets that were 30% smaller when using the trans-ethnic as opposed to the EUR-only results. We explored the clinical significance and predictive value of trans-ethnic variants in multiple populations and compared genetic architecture and the effect of natural selection on these blood phenotypes between populations. Altogether, our results for hematological traits highlight the value of a more global representation of populations in genetic studies.

Published
2020

25. Interrogation of human hematopoiesis at single-cell and single-variant resolution

Author

Ulirsch, Jacob C, Lareau, Caleb A, Bao, Erik L, Ludwig, Leif S, Guo, Michael H, Benner, Christian, Satpathy, Ansuman T, Kartha, Vinay K, Salem, Rany M, Hirschhorn, Joel N, Finucane, Hilary K, Aryee, Martin J, Buenrostro, Jason D, and Sankaran, Vijay G

Subjects
Human Genome, Genetics, Stem Cell Research - Nonembryonic - Non-Human, Stem Cell Research, Biotechnology, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, 2.1 Biological and endogenous factors, Generic health relevance, Cell Lineage, Chromatin, Chromosome Mapping, Epigenomics, Genome-Wide Association Study, Hematopoiesis, Humans, Linkage Disequilibrium, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Widespread linkage disequilibrium and incomplete annotation of cell-to-cell state variation represent substantial challenges to elucidating mechanisms of trait-associated genetic variation. Here we perform genetic fine-mapping for blood cell traits in the UK Biobank to identify putative causal variants. These variants are enriched in genes encoding proteins in trait-relevant biological pathways and in accessible chromatin of hematopoietic progenitors. For regulatory variants, we explore patterns of developmental enhancer activity, predict molecular mechanisms, and identify likely target genes. In several instances, we localize multiple independent variants to the same regulatory element or gene. We further observe that variants with pleiotropic effects preferentially act in common progenitor populations to direct the production of distinct lineages. Finally, we leverage fine-mapped variants in conjunction with continuous epigenomic annotations to identify trait-cell type enrichments within closely related populations and in single cells. Our study provides a comprehensive framework for single-variant and single-cell analyses of genetic associations.

Published
2019

27. Runx3 drives a CD8+ T cell tissue residency program that is absent in CD4+ T cells

Author

Fonseca, Raíssa, Burn, Thomas N., Gandolfo, Luke C., Devi, Sapna, Park, Simone L., Obers, Andreas, Evrard, Maximilien, Christo, Susan N., Buquicchio, Frank A., Lareau, Caleb A., McDonald, Keely M., Sandford, Sarah K., Zamudio, Natasha M., Zanluqui, Nagela G., Zaid, Ali, Speed, Terence P., Satpathy, Ansuman T., Mueller, Scott N., Carbone, Francis R., and Mackay, Laura K.

Published
2022
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28. Mitochondrial variant enrichment from high-throughput single-cell RNA sequencing resolves clonal populations

Author

Miller, Tyler E., Lareau, Caleb A., Verga, Julia A., DePasquale, Erica A. K., Liu, Vincent, Ssozi, Daniel, Sandor, Katalin, Yin, Yajie, Ludwig, Leif S., El Farran, Chadi A., Morgan, Duncan M., Satpathy, Ansuman T., Griffin, Gabriel K., Lane, Andrew A., Love, J. Christopher, Bernstein, Bradley E., Sankaran, Vijay G., and van Galen, Peter

Published
2022
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29. Congenital anemia reveals distinct targeting mechanisms for master transcription factor GATA1

Author

Ludwig, Leif S., Lareau, Caleb A., Bao, Erik L., Liu, Nan, Utsugisawa, Taiju, Tseng, Alex M., Myers, Samuel A., Verboon, Jeffrey M., Ulirsch, Jacob C., Luo, Wendy, Muus, Christoph, Fiorini, Claudia, Olive, Meagan E., Vockley, Christopher M., Munschauer, Mathias, Hunter, Abigail, Ogura, Hiromi, Yamamoto, Toshiyuki, Inada, Hiroko, Nakagawa, Shinichiro, Ohzono, Shuichi, Subramanian, Vidya, Chiarle, Roberto, Glader, Bertil, Carr, Steven A., Aryee, Martin J., Kundaje, Anshul, Orkin, Stuart H., Regev, Aviv, McCavit, Timothy L., Kanno, Hitoshi, and Sankaran, Vijay G.

Published
2022
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32. Transcript-indexed ATAC-seq for precision immune profiling

Author

Satpathy, Ansuman T, Saligrama, Naresha, Buenrostro, Jason D, Wei, Yuning, Wu, Beijing, Rubin, Adam J, Granja, Jeffrey M, Lareau, Caleb A, Li, Rui, Qi, Yanyan, Parker, Kevin R, Mumbach, Maxwell R, Serratelli, William S, Gennert, David G, Schep, Alicia N, Corces, M Ryan, Khodadoust, Michael S, Kim, Youn H, Khavari, Paul A, Greenleaf, William J, Davis, Mark M, and Chang, Howard Y

Subjects
Genetics, Human Genome, Biotechnology, Hematology, Vaccine Related, Clinical Research, Rare Diseases, Cancer, Immunization, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Inflammatory and immune system, CD4-Positive T-Lymphocytes, Cell Line, Transformed, Chromatin, Clone Cells, Epigenomics, High-Throughput Nucleotide Sequencing, Humans, Immunity, Jurkat Cells, Leukemia, RNA, Messenger, Receptors, Antigen, T-Cell, Single-Cell Analysis, Transposases, Medical and Health Sciences, Immunology
Abstract

T cells create vast amounts of diversity in the genes that encode their T cell receptors (TCRs), which enables individual clones to recognize specific peptide-major histocompatibility complex (MHC) ligands. Here we combined sequencing of the TCR-encoding genes with assay for transposase-accessible chromatin with sequencing (ATAC-seq) analysis at the single-cell level to provide information on the TCR specificity and epigenomic state of individual T cells. By using this approach, termed transcript-indexed ATAC-seq (T-ATAC-seq), we identified epigenomic signatures in immortalized leukemic T cells, primary human T cells from healthy volunteers and primary leukemic T cells from patient samples. In peripheral blood CD4+ T cells from healthy individuals, we identified cis and trans regulators of naive and memory T cell states and found substantial heterogeneity in surface-marker-defined T cell populations. In patients with a leukemic form of cutaneous T cell lymphoma, T-ATAC-seq enabled identification of leukemic and nonleukemic regulatory pathways in T cells from the same individual by allowing separation of the signals that arose from the malignant clone from the background T cell noise. Thus, T-ATAC-seq is a new tool that enables analysis of epigenomic landscapes in clonal T cells and should be valuable for studies of T cell malignancy, immunity and immunotherapy.

Published
2018

34. Author Correction: Functional dissection of inherited non-coding variation influencing multiple myeloma risk

Author

Ajore, Ram, Niroula, Abhishek, Pertesi, Maroulio, Cafaro, Caterina, Thodberg, Malte, Went, Molly, Bao, Erik L., Duran-Lozano, Laura, Lopez de Lapuente Portilla, Aitzkoa, Olafsdottir, Thorunn, Ugidos-Damboriena, Nerea, Magnusson, Olafur, Samur, Mehmet, Lareau, Caleb A., Halldorsson, Gisli H., Thorleifsson, Gudmar, Norddahl, Gudmundur L., Gunnarsdottir, Kristbjorg, Försti, Asta, Goldschmidt, Hartmut, Hemminki, Kari, van Rhee, Frits, Kimber, Scott, Sperling, Adam S., Kaiser, Martin, Anderson, Kenneth, Jonsdottir, Ingileif, Munshi, Nikhil, Rafnar, Thorunn, Waage, Anders, Weinhold, Niels, Thorsteinsdottir, Unnur, Sankaran, Vijay G., Stefansson, Kari, Houlston, Richard, and Nilsson, Björn

Published
2022
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35. Functional dissection of inherited non-coding variation influencing multiple myeloma risk

Author

Ajore, Ram, Niroula, Abhishek, Pertesi, Maroulio, Cafaro, Caterina, Thodberg, Malte, Went, Molly, Bao, Erik L., Duran-Lozano, Laura, Lopez de Lapuente Portilla, Aitzkoa, Olafsdottir, Thorunn, Ugidos-Damboriena, Nerea, Magnusson, Olafur, Samur, Mehmet, Lareau, Caleb A., Halldorsson, Gisli H., Thorleifsson, Gudmar, Norddahl, Gudmundur L., Gunnarsdottir, Kristbjorg, Försti, Asta, Goldschmidt, Hartmut, Hemminki, Kari, van Rhee, Frits, Kimber, Scott, Sperling, Adam S., Kaiser, Martin, Anderson, Kenneth, Jonsdottir, Ingileif, Munshi, Nikhil, Rafnar, Thorunn, Waage, Anders, Weinhold, Niels, Thorsteinsdottir, Unnur, Sankaran, Vijay G., Stefansson, Kari, Houlston, Richard, and Nilsson, Björn

Published
2022
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37. STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma

Author

Adane, Biniam, Alexe, Gabriela, Seong, Bo Kyung A., Lu, Diana, Hwang, Elizabeth E., Hnisz, Denes, Lareau, Caleb A., Ross, Linda, Lin, Shan, Dela Cruz, Filemon S., Richardson, Melissa, Weintraub, Abraham S., Wang, Sarah, Iniguez, Amanda Balboni, Dharia, Neekesh V., Conway, Amy Saur, Robichaud, Amanda L., Tanenbaum, Benjamin, Krill-Burger, John M., Vazquez, Francisca, Schenone, Monica, Berman, Jason N., Kung, Andrew L., Carr, Steven A., Aryee, Martin J., Young, Richard A., Crompton, Brian D., and Stegmaier, Kimberly

Published
2021
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39. Scalable, multimodal profiling of chromatin accessibility, gene expression and protein levels in single cells

Author

Mimitou, Eleni P., Lareau, Caleb A., Chen, Kelvin Y., Zorzetto-Fernandes, Andre L., Hao, Yuhan, Takeshima, Yusuke, Luo, Wendy, Huang, Tse-Shun, Yeung, Bertrand Z., Papalexi, Efthymia, Thakore, Pratiksha I., Kibayashi, Tatsuya, Wing, James Badger, Hata, Mayu, Satija, Rahul, Nazor, Kristopher L., Sakaguchi, Shimon, Ludwig, Leif S., Sankaran, Vijay G., Regev, Aviv, and Smibert, Peter

Published
2021
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41. Identifying optimal tumor-associated antigen combinations with single-cell genomics to enable multi-targeting therapies.

Author

Nix, Matthew A., Lareau, Caleb A., Verboon, Jeffrey, and Kugler, David G.

Subjects
BOOLEAN functions, IMMUNOTECHNOLOGY, IMMUNOGLOBULINS, ANTIGENS, GENOMICS
Abstract

Targeted antibody-based therapy for oncology represents a highly efficacious approach that has demonstrated robust responses against single tumor-associated antigen (TAA) targets. However, tumor heterogeneity presents a major obstacle for targeting most solid tumors due to a lack of single targets that possess the right on-tumor/off-tumor expression profile required for adequate therapeutic index. Multi-targeting antibodies that engage two TAAs simultaneously may address this challenge through Boolean logic-gating function by improving both therapeutic specificity and efficacy. In addition to the complex engineering of multi-targeting antibodies for ideal logic-gate function, selecting optimal TAA combinations ab initio is the critical step to initiate preclinical development but remains largely unexplored with modern data-generation platforms. Here, we propose that single-cell atlases of both primary tumor and normal tissues are uniquely positioned to unveil optimal target combinations for multi-targeting antibody therapeutics. We review the most recent progress in multi-targeting antibody clinical development, as well as the designs of current TAA combinations currently exploited. Ultimately, we describe how multi-targeting antibodies tuned to target pairs nominated through a data-driven process are poised to revolutionize therapeutic safety and efficacy, particularly for difficult-to-treat solid tumors. [ABSTRACT FROM AUTHOR]

Published
2024
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44. The Polygenic and Monogenic Basis of Blood Traits and Diseases

Author

Vuckovic, Dragana, Bao, Erik L., Akbari, Parsa, Lareau, Caleb A., Mousas, Abdou, Jiang, Tao, Chen, Ming-Huei, Raffield, Laura M., Tardaguila, Manuel, Huffman, Jennifer E., Ritchie, Scott C., Megy, Karyn, Ponstingl, Hannes, Penkett, Christopher J., Albers, Patrick K., Wigdor, Emilie M., Sakaue, Saori, Moscati, Arden, Manansala, Regina, Lo, Ken Sin, Qian, Huijun, Akiyama, Masato, Bartz, Traci M., Ben-Shlomo, Yoav, Beswick, Andrew, Bork-Jensen, Jette, Bottinger, Erwin P., Brody, Jennifer A., van Rooij, Frank J.A., Chitrala, Kumaraswamy N., Wilson, Peter W.F., Choquet, Hélène, Danesh, John, Di Angelantonio, Emanuele, Dimou, Niki, Ding, Jingzhong, Elliott, Paul, Esko, Tõnu, Evans, Michele K., Felix, Stephan B., Floyd, James S., Broer, Linda, Grarup, Niels, Guo, Michael H., Guo, Qi, Greinacher, Andreas, Haessler, Jeff, Hansen, Torben, Howson, Joanna M.M., Huang, Wei, Jorgenson, Eric, Kacprowski, Tim, Kähönen, Mika, Kamatani, Yoichiro, Kanai, Masahiro, Karthikeyan, Savita, Koskeridis, Fotios, Lange, Leslie A., Lehtimäki, Terho, Linneberg, Allan, Liu, Yongmei, Lyytikäinen, Leo-Pekka, Manichaikul, Ani, Matsuda, Koichi, Mohlke, Karen L., Mononen, Nina, Murakami, Yoshinori, Nadkarni, Girish N., Nikus, Kjell, Pankratz, Nathan, Pedersen, Oluf, Preuss, Michael, Psaty, Bruce M., Raitakari, Olli T., Rich, Stephen S., Rodriguez, Benjamin A.T., Rosen, Jonathan D., Rotter, Jerome I., Schubert, Petra, Spracklen, Cassandra N., Surendran, Praveen, Tang, Hua, Tardif, Jean-Claude, Ghanbari, Mohsen, Völker, Uwe, Völzke, Henry, Watkins, Nicholas A., Weiss, Stefan, Cai, Na, Kundu, Kousik, Watt, Stephen B., Walter, Klaudia, Zonderman, Alan B., Cho, Kelly, Li, Yun, Loos, Ruth J.F., Knight, Julian C., Georges, Michel, Stegle, Oliver, Evangelou, Evangelos, Okada, Yukinori, Roberts, David J., Inouye, Michael, Johnson, Andrew D., Auer, Paul L., Astle, William J., Reiner, Alexander P., Butterworth, Adam S., Ouwehand, Willem H., Lettre, Guillaume, Sankaran, Vijay G., and Soranzo, Nicole

Published
2020
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46. Transcript-specific enrichment enables profiling rare cell states via scRNA-seq

Author

Abay, Tsion, primary, Stickels, Robert R., additional, Takizawa, Meril T., additional, Nalbant, Benan N., additional, Hsieh, Yu-Hsin, additional, Hwang, Sidney, additional, Snopkowski, Catherine, additional, Yu, Kenny Kwok Hei, additional, Abou-Mrad, Zaki, additional, Tabar, Viviane, additional, Ludwig, Leif S., additional, Chaligne, Ronan, additional, Satpathy, Ansuman T., additional, and Lareau, Caleb A., additional

Published
2024
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49. The SARS-CoV-2 RNA–protein interactome in infected human cells

Author

Schmidt, Nora, Lareau, Caleb A., Keshishian, Hasmik, Ganskih, Sabina, Schneider, Cornelius, Hennig, Thomas, Melanson, Randy, Werner, Simone, Wei, Yuanjie, Zimmer, Matthias, Ade, Jens, Kirschner, Luisa, Zielinski, Sebastian, Dölken, Lars, Lander, Eric S., Caliskan, Neva, Fischer, Utz, Vogel, Jörg, Carr, Steven A., Bodem, Jochen, and Munschauer, Mathias

Published
2021
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