Search

Your search keyword '"Kharchenko, Peter V."' showing total 531 results
Start Over Author "Kharchenko, Peter V."
531 results on '"Kharchenko, Peter V."'

1. Joint single-cell genetic and transcriptomic analysis reveal pre-malignant SCP-like subclones in human neuroblastoma

Author

Olsen, Thale K., Otte, Jörg, Mei, Shenglin, Embaie, Bethel Tesfai, Kameneva, Polina, Cheng, Huaitao, Gao, Teng, Zachariadis, Vasilios, Tsea, Ioanna, Björklund, Åsa, Kryukov, Emil, Hou, Ziyi, Johansson, Anna, Sundström, Erik, Martinsson, Tommy, Fransson, Susanne, Stenman, Jakob, Fard, Shahrzad Shirazi, Johnsen, John Inge, Kogner, Per, Adameyko, Igor, Enge, Martin, Kharchenko, Peter V., and Baryawno, Ninib

Published
2024
Full Text
View/download PDF

4. An atlas of healthy and injured cell states and niches in the human kidney

Author

Lake, Blue B., Menon, Rajasree, Winfree, Seth, Hu, Qiwen, Melo Ferreira, Ricardo, Kalhor, Kian, Barwinska, Daria, Otto, Edgar A., Ferkowicz, Michael, Diep, Dinh, Plongthongkum, Nongluk, Knoten, Amanda, Urata, Sarah, Mariani, Laura H., Naik, Abhijit S., Eddy, Sean, Zhang, Bo, Wu, Yan, Salamon, Diane, Williams, James C., Wang, Xin, Balderrama, Karol S., Hoover, Paul J., Murray, Evan, Marshall, Jamie L., Noel, Teia, Vijayan, Anitha, Hartman, Austin, Chen, Fei, Waikar, Sushrut S., Rosas, Sylvia E., Wilson, Francis P., Palevsky, Paul M., Kiryluk, Krzysztof, Sedor, John R., Toto, Robert D., Parikh, Chirag R., Kim, Eric H., Satija, Rahul, Greka, Anna, Macosko, Evan Z., Kharchenko, Peter V., Gaut, Joseph P., Hodgin, Jeffrey B., Eadon, Michael T., Dagher, Pierre C., El-Achkar, Tarek M., Zhang, Kun, Kretzler, Matthias, and Jain, Sanjay

Published
2023
Full Text
View/download PDF

5. Cell types and ontologies of the Human Cell Atlas

Author

Osumi-Sutherland, David, Xu, Chuan, Keays, Maria, Kharchenko, Peter V., Regev, Aviv, Lein, Ed, and Teichmann, Sarah A.

Subjects
Quantitative Biology - Cell Behavior
Abstract

Massive single-cell profiling efforts have accelerated our discovery of the cellular composition of the human body, while at the same time raising the need to formalise this new knowledge. Here, we review current cell ontology efforts to harmonise and integrate different sources of annotations of cell types and states. We illustrate with examples how a unified ontology can consolidate and advance our understanding of cell types across scientific communities and biological domains.

Published
2021
Full Text
View/download PDF

6. A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex

Author

Yao, Zizhen, Liu, Hanqing, Xie, Fangming, Fischer, Stephan, Adkins, Ricky S, Aldridge, Andrew I, Ament, Seth A, Bartlett, Anna, Behrens, M Margarita, Van den Berge, Koen, Bertagnolli, Darren, de Bézieux, Hector Roux, Biancalani, Tommaso, Booeshaghi, A Sina, Bravo, Héctor Corrada, Casper, Tamara, Colantuoni, Carlo, Crabtree, Jonathan, Creasy, Heather, Crichton, Kirsten, Crow, Megan, Dee, Nick, Dougherty, Elizabeth L, Doyle, Wayne I, Dudoit, Sandrine, Fang, Rongxin, Felix, Victor, Fong, Olivia, Giglio, Michelle, Goldy, Jeff, Hawrylycz, Mike, Herb, Brian R, Hertzano, Ronna, Hou, Xiaomeng, Hu, Qiwen, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, Li, Yang Eric, Lucero, Jacinta D, Luo, Chongyuan, Mahurkar, Anup, McMillen, Delissa, Nadaf, Naeem M, Nery, Joseph R, Nguyen, Thuc Nghi, Niu, Sheng-Yong, Ntranos, Vasilis, Orvis, Joshua, Osteen, Julia K, Pham, Thanh, Pinto-Duarte, Antonio, Poirion, Olivier, Preissl, Sebastian, Purdom, Elizabeth, Rimorin, Christine, Risso, Davide, Rivkin, Angeline C, Smith, Kimberly, Street, Kelly, Sulc, Josef, Svensson, Valentine, Tieu, Michael, Torkelson, Amy, Tung, Herman, Vaishnav, Eeshit Dhaval, Vanderburg, Charles R, van Velthoven, Cindy, Wang, Xinxin, White, Owen R, Huang, Z Josh, Kharchenko, Peter V, Pachter, Lior, Ngai, John, Regev, Aviv, Tasic, Bosiljka, Welch, Joshua D, Gillis, Jesse, Macosko, Evan Z, Ren, Bing, Ecker, Joseph R, Zeng, Hongkui, and Mukamel, Eran A

Subjects
Human Genome, Neurosciences, Genetics, Bioengineering, Biotechnology, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Animals, Atlases as Topic, Datasets as Topic, Epigenesis, Genetic, Epigenomics, Female, Gene Expression Profiling, Male, Mice, Motor Cortex, Neurons, Organ Specificity, Reproducibility of Results, Single-Cell Analysis, Transcriptome, General Science & Technology
Abstract

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain1-3. With the proliferation of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of cell-type organization. Here we generated transcriptomes and epigenomes from more than 500,000 individual cells in the mouse primary motor cortex, a structure that has an evolutionarily conserved role in locomotion. We developed computational and statistical methods to integrate multimodal data and quantitatively validate cell-type reproducibility. The resulting reference atlas-containing over 56 neuronal cell types that are highly replicable across analysis methods, sequencing technologies and modalities-is a comprehensive molecular and genomic account of the diverse neuronal and non-neuronal cell types in the mouse primary motor cortex. The atlas includes a population of excitatory neurons that resemble pyramidal cells in layer 4 in other cortical regions4. We further discovered thousands of concordant marker genes and gene regulatory elements for these cell types. Our results highlight the complex molecular regulation of cell types in the brain and will directly enable the design of reagents to target specific cell types in the mouse primary motor cortex for functional analysis.

Published
2021

7. Comparative cellular analysis of motor cortex in human, marmoset and mouse

Author

Bakken, Trygve E, Jorstad, Nikolas L, Hu, Qiwen, Lake, Blue B, Tian, Wei, Kalmbach, Brian E, Crow, Megan, Hodge, Rebecca D, Krienen, Fenna M, Sorensen, Staci A, Eggermont, Jeroen, Yao, Zizhen, Aevermann, Brian D, Aldridge, Andrew I, Bartlett, Anna, Bertagnolli, Darren, Casper, Tamara, Castanon, Rosa G, Crichton, Kirsten, Daigle, Tanya L, Dalley, Rachel, Dee, Nick, Dembrow, Nikolai, Diep, Dinh, Ding, Song-Lin, Dong, Weixiu, Fang, Rongxin, Fischer, Stephan, Goldman, Melissa, Goldy, Jeff, Graybuck, Lucas T, Herb, Brian R, Hou, Xiaomeng, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, van Lew, Baldur, Li, Yang Eric, Liu, Christine S, Liu, Hanqing, Lucero, Jacinta D, Mahurkar, Anup, McMillen, Delissa, Miller, Jeremy A, Moussa, Marmar, Nery, Joseph R, Nicovich, Philip R, Niu, Sheng-Yong, Orvis, Joshua, Osteen, Julia K, Owen, Scott, Palmer, Carter R, Pham, Thanh, Plongthongkum, Nongluk, Poirion, Olivier, Reed, Nora M, Rimorin, Christine, Rivkin, Angeline, Romanow, William J, Sedeño-Cortés, Adriana E, Siletti, Kimberly, Somasundaram, Saroja, Sulc, Josef, Tieu, Michael, Torkelson, Amy, Tung, Herman, Wang, Xinxin, Xie, Fangming, Yanny, Anna Marie, Zhang, Renee, Ament, Seth A, Behrens, M Margarita, Bravo, Hector Corrada, Chun, Jerold, Dobin, Alexander, Gillis, Jesse, Hertzano, Ronna, Hof, Patrick R, Höllt, Thomas, Horwitz, Gregory D, Keene, C Dirk, Kharchenko, Peter V, Ko, Andrew L, Lelieveldt, Boudewijn P, Luo, Chongyuan, Mukamel, Eran A, Pinto-Duarte, António, Preissl, Sebastian, Regev, Aviv, Ren, Bing, Scheuermann, Richard H, Smith, Kimberly, Spain, William J, White, Owen R, Koch, Christof, Hawrylycz, Michael, Tasic, Bosiljka, Macosko, Evan Z, McCarroll, Steven A, and Ting, Jonathan T

Subjects
Human Genome, Neurosciences, Genetics, Biotechnology, Underpinning research, 1.1 Normal biological development and functioning, Neurological, Animals, Atlases as Topic, Callithrix, Epigenesis, Genetic, Epigenomics, Female, GABAergic Neurons, Gene Expression Profiling, Glutamates, Humans, In Situ Hybridization, Fluorescence, Male, Mice, Middle Aged, Motor Cortex, Neurons, Organ Specificity, Phylogeny, Single-Cell Analysis, Species Specificity, Transcriptome, General Science & Technology
Abstract

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

Published
2021

8. Dissecting the immune suppressive human prostate tumor microenvironment via integrated single-cell and spatial transcriptomic analyses

Author

Hirz, Taghreed, Mei, Shenglin, Sarkar, Hirak, Kfoury, Youmna, Wu, Shulin, Verhoeven, Bronte M., Subtelny, Alexander O., Zlatev, Dimitar V., Wszolek, Matthew W., Salari, Keyan, Murray, Evan, Chen, Fei, Macosko, Evan Z., Wu, Chin-Lee, Scadden, David T., Dahl, Douglas M., Baryawno, Ninib, Saylor, Philip J., Kharchenko, Peter V., and Sykes, David B.

Published
2023
Full Text
View/download PDF

9. Population sequencing data reveal a compendium of mutational processes in the human germ line.

Author

Seplyarskiy, Vladimir B, Soldatov, Ruslan A, Koch, Evan, McGinty, Ryan J, Goldmann, Jakob M, Hernandez, Ryan D, Barnes, Kathleen, Correa, Adolfo, Burchard, Esteban G, Ellinor, Patrick T, McGarvey, Stephen T, Mitchell, Braxton D, Vasan, Ramachandran S, Redline, Susan, Silverman, Edwin, Weiss, Scott T, Arnett, Donna K, Blangero, John, Boerwinkle, Eric, He, Jiang, Montgomery, Courtney, Rao, DC, Rotter, Jerome I, Taylor, Kent D, Brody, Jennifer A, Chen, Yii-Der Ida, de Las Fuentes, Lisa, Hwu, Chii-Min, Rich, Stephen S, Manichaikul, Ani W, Mychaleckyj, Josyf C, Palmer, Nicholette D, Smith, Jennifer A, Kardia, Sharon LR, Peyser, Patricia A, Bielak, Lawrence F, O'Connor, Timothy D, Emery, Leslie S, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Population Genetics Working Group, Gilissen, Christian, Wong, Wendy SW, Kharchenko, Peter V, and Sunyaev, Shamil

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Population Genetics Working Group, Germ Cells, Oocytes, Humans, DNA Damage, DNA Mutational Analysis, DNA Replication, Transcription, Genetic, Mutagenesis, CpG Islands, Long Interspersed Nucleotide Elements, Germ-Line Mutation, Genome, Human, Algorithms, Genetic Variation, DNA Demethylation, Human Genome, Genetics, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, 2.1 Biological and endogenous factors, Generic health relevance, General Science & Technology
Abstract

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

Published
2021

12. Dental cell type atlas reveals stem and differentiated cell types in mouse and human teeth.

Author

Krivanek, Jan, Soldatov, Ruslan A, Kastriti, Maria Eleni, Chontorotzea, Tatiana, Herdina, Anna Nele, Petersen, Julian, Szarowska, Bara, Landova, Marie, Matejova, Veronika Kovar, Holla, Lydie Izakovicova, Kuchler, Ulrike, Zdrilic, Ivana Vidovic, Vijaykumar, Anushree, Balic, Anamaria, Marangoni, Pauline, Klein, Ophir D, Neves, Vitor CM, Yianni, Val, Sharpe, Paul T, Harkany, Tibor, Metscher, Brian D, Bajénoff, Marc, Mina, Mina, Fried, Kaj, Kharchenko, Peter V, and Adameyko, Igor

Subjects
Odontoblasts, Epithelial Cells, Stem Cells, Tooth, Incisor, Molar, Mesoderm, Animals, Mice, Inbred C57BL, Humans, Mice, Models, Animal, Cell Differentiation, Gene Expression Regulation, Developmental, Genetic Heterogeneity, Adolescent, Adult, Female, Male, Young Adult
Abstract

Understanding cell types and mechanisms of dental growth is essential for reconstruction and engineering of teeth. Therefore, we investigated cellular composition of growing and non-growing mouse and human teeth. As a result, we report an unappreciated cellular complexity of the continuously-growing mouse incisor, which suggests a coherent model of cell dynamics enabling unarrested growth. This model relies on spatially-restricted stem, progenitor and differentiated populations in the epithelial and mesenchymal compartments underlying the coordinated expansion of two major branches of pulpal cells and diverse epithelial subtypes. Further comparisons of human and mouse teeth yield both parallelisms and differences in tissue heterogeneity and highlight the specifics behind growing and non-growing modes. Despite being similar at a coarse level, mouse and human teeth reveal molecular differences and species-specific cell subtypes suggesting possible evolutionary divergence. Overall, here we provide an atlas of human and mouse teeth with a focus on growth and differentiation.

Published
2020

13. Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to the graft-versus-leukemia effect

Author

Bachireddy, Pavan, Ennis, Christina, Nguyen, Vinhkhang N, Gohil, Satyen H, Clement, Kendell, Shukla, Sachet A, Forman, Juliet, Barkas, Nikolaos, Freeman, Samuel, Bavli, Natalie, Elagina, Liudmila, Leshchiner, Ignaty, Mohammad, Arman W, Mathewson, Nathan D, Keskin, Derin B, Rassenti, Laura Z, Kipps, Thomas J, Brown, Jennifer R, Getz, Gad, Ho, Vincent T, Gnirke, Andreas, Neuberg, Donna, Soiffer, Robert J, Ritz, Jerome, Alyea, Edwin P, Kharchenko, Peter V, and Wu, Catherine J

Subjects
Stem Cell Research, Hematology, Rare Diseases, Cancer, Stem Cell Research - Nonembryonic - Human, Lymphoma, Transplantation, Genetics, Stem Cell Research - Nonembryonic - Non-Human, Graft vs Host Disease, Graft vs Leukemia Effect, HLA Antigens, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Transplantation, Homologous, Biological Sciences, Medical and Health Sciences
Abstract

Leukemic relapse remains a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis for relapse of advanced lymphoid malignancies remains incompletely understood and may involve escape from the graft-versus-leukemia (GvL) effect. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features influence transplant outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic, and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post-HSCT relapse are shaped by distinct molecular dynamics. Early relapses after allo-HSCT exhibited notable genetic stability; single CLL cell transcriptional analysis demonstrated a cellular heterogeneity that was static over time. In contrast, CLL cells relapsing late after allo-HSCT displayed notable genetic evolution and evidence of neoantigen depletion, consistent with marked single-cell transcriptional shifts that were unique to each patient. We observed a greater rate of epigenetic change for late relapses not seen in early relapses or relapses after chemotherapy alone, suggesting that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for human leukocyte antigen (HLA) loss was observed, even when present in pretransplant subpopulations. Gain of stem cell modules was a common signature associated with leukemia relapse regardless of posttransplant relapse kinetics. These data elucidate the biological pathways that underlie GvL resistance and posttransplant relapse.

Published
2020

17. Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain

Author

Lake, Blue B, Chen, Song, Sos, Brandon C, Fan, Jean, Kaeser, Gwendolyn E, Yung, Yun C, Duong, Thu E, Gao, Derek, Chun, Jerold, Kharchenko, Peter V, and Zhang, Kun

Subjects
Neurological, Generic health relevance, Adult, Brain, Cerebellum, Epigenesis, Genetic, Frontal Lobe, High-Throughput Nucleotide Sequencing, Humans, Sequence Analysis, RNA, Single-Cell Analysis, Transcriptome, Visual Cortex
Abstract

Detailed characterization of the cell types in the human brain requires scalable experimental approaches to examine multiple aspects of the molecular state of individual cells, as well as computational integration of the data to produce unified cell-state annotations. Here we report improved high-throughput methods for single-nucleus droplet-based sequencing (snDrop-seq) and single-cell transposome hypersensitive site sequencing (scTHS-seq). We used each method to acquire nuclear transcriptomic and DNA accessibility maps for >60,000 single cells from human adult visual cortex, frontal cortex, and cerebellum. Integration of these data revealed regulatory elements and transcription factors that underlie cell-type distinctions, providing a basis for the study of complex processes in the brain, such as genetic programs that coordinate adult remyelination. We also mapped disease-associated risk variants to specific cellular populations, which provided insights into normal and pathogenic cellular processes in the human brain. This integrative multi-omics approach permits more detailed single-cell interrogation of complex organs and tissues.

Published
2018

20. Rewiring of human neurodevelopmental gene regulatory programs by human accelerated regions

Author

Girskis, Kelly M., Stergachis, Andrew B., DeGennaro, Ellen M., Doan, Ryan N., Qian, Xuyu, Johnson, Matthew B., Wang, Peter P., Sejourne, Gabrielle M., Nagy, M. Aurel, Pollina, Elizabeth A., Sousa, André M.M., Shin, Taehwan, Kenny, Connor J., Scotellaro, Julia L., Debo, Brian M., Gonzalez, Dilenny M., Rento, Lariza M., Yeh, Rebecca C., Song, Janet H.T., Beaudin, Marc, Fan, Jean, Kharchenko, Peter V., Sestan, Nenad, Greenberg, Michael E., and Walsh, Christopher A.

Published
2021
Full Text
View/download PDF

22. A comparative strategy for single-nucleus and single-cell transcriptomes confirms accuracy in predicted cell-type expression from nuclear RNA.

Author

Lake, Blue B, Codeluppi, Simone, Yung, Yun C, Gao, Derek, Chun, Jerold, Kharchenko, Peter V, Linnarsson, Sten, and Zhang, Kun

Subjects
Cerebral Cortex, Neurons, Cell Nucleus, Animals, Mice, Gene Expression Profiling, Organ Specificity, Gene Expression Regulation, Female, Male, Single-Cell Analysis, High-Throughput Nucleotide Sequencing, Transcriptome, Human Genome, Genetics, Biotechnology, 1.1 Normal biological development and functioning, Biochemistry and Cell Biology, Other Physical Sciences
Abstract

Significant heterogeneities in gene expression among individual cells are typically interrogated using single whole cell approaches. However, tissues that have highly interconnected processes, such as in the brain, present unique challenges. Single-nucleus RNA sequencing (SNS) has emerged as an alternative method of assessing a cell's transcriptome through the use of isolated nuclei. However, studies directly comparing expression data between nuclei and whole cells are lacking. Here, we have characterized nuclear and whole cell transcriptomes in mouse single neurons and provided a normalization strategy to reduce method-specific differences related to the length of genic regions. We confirmed a high concordance between nuclear and whole cell transcriptomes in the expression of cell type and metabolic modeling markers, but less so for a subset of genes associated with mitochondrial respiration. Therefore, our results indicate that single-nucleus transcriptome sequencing provides an effective means to profile cell type expression dynamics in previously inaccessible tissues.

Published
2017

24. Single-cell transcriptomics of human embryos identifies multiple sympathoblast lineages with potential implications for neuroblastoma origin

Author

Kameneva, Polina, Artemov, Artem V., Kastriti, Maria Eleni, Faure, Louis, Olsen, Thale K., Otte, Jörg, Erickson, Alek, Semsch, Bettina, Andersson, Emma R., Ratz, Michael, Frisén, Jonas, Tischler, Arthur S., de Krijger, Ronald R., Bouderlique, Thibault, Akkuratova, Natalia, Vorontsova, Maria, Gusev, Oleg, Fried, Kaj, Sundström, Erik, Mei, Shenglin, Kogner, Per, Baryawno, Ninib, Kharchenko, Peter V., and Adameyko, Igor

Published
2021
Full Text
View/download PDF

25. 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, Lymphoma, Genetics, Clinical Research, Cancer, Rare Diseases, Hematology, 2.1 Biological and endogenous factors, Aetiology, 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

26. Cell-Type-Specific Alternative Splicing Governs Cell Fate in the Developing Cerebral Cortex

Author

Zhang, Xiaochang, Chen, Ming Hui, Wu, Xuebing, Kodani, Andrew, Fan, Jean, Doan, Ryan, Ozawa, Manabu, Ma, Jacqueline, Yoshida, Nobuaki, Reiter, Jeremy F, Black, Douglas L, Kharchenko, Peter V, Sharp, Phillip A, and Walsh, Christopher A

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Stem Cell Research - Nonembryonic - Non-Human, Neurosciences, Brain Disorders, Stem Cell Research, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Alternative Splicing, Animals, Centrosome, Cerebral Cortex, Cytoskeletal Proteins, Exons, Heterogeneous-Nuclear Ribonucleoproteins, Humans, Mice, Neural Stem Cells, Neurogenesis, Neurons, Nuclear Proteins, Polypyrimidine Tract-Binding Protein, Protein Domains, Protein Isoforms, RNA Splicing Factors, Ninein, Ptbp1, Rbfox, filamin A, microcephaly, mother centriole, periventricular nodular heterotopia, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Alternative splicing is prevalent in the mammalian brain. To interrogate the functional role of alternative splicing in neural development, we analyzed purified neural progenitor cells (NPCs) and neurons from developing cerebral cortices, revealing hundreds of differentially spliced exons that preferentially alter key protein domains-especially in cytoskeletal proteins-and can harbor disease-causing mutations. We show that Ptbp1 and Rbfox proteins antagonistically govern the NPC-to-neuron transition by regulating neuron-specific exons. Whereas Ptbp1 maintains apical progenitors partly through suppressing a poison exon of Flna in NPCs, Rbfox proteins promote neuronal differentiation by switching Ninein from a centrosomal splice form in NPCs to a non-centrosomal isoform in neurons. We further uncover an intronic human mutation within a PTBP1-binding site that disrupts normal skipping of the FLNA poison exon in NPCs and causes a brain-specific malformation. Our study indicates that dynamic control of alternative splicing governs cell fate in cerebral cortical development.

Published
2016

27. Characterizing transcriptional heterogeneity through pathway and gene set overdispersion analysis

Author

Fan, Jean, Salathia, Neeraj, Liu, Rui, Kaeser, Gwendolyn E, Yung, Yun C, Herman, Joseph L, Kaper, Fiona, Fan, Jian-Bing, Zhang, Kun, Chun, Jerold, and Kharchenko, Peter V

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biotechnology, Genetics, Animals, Cells, Cultured, Computer Simulation, Gene Expression Profiling, Mice, Models, Biological, Models, Statistical, Neurons, Proteome, Sequence Analysis, RNA, Signal Transduction, Transcription, Genetic, Transcriptome, Technology, Medical and Health Sciences, Developmental Biology, Biological sciences
Abstract

The transcriptional state of a cell reflects a variety of biological factors, from cell-type-specific features to transient processes such as the cell cycle, all of which may be of interest. However, identifying such aspects from noisy single-cell RNA-seq data remains challenging. We developed pathway and gene set overdispersion analysis (PAGODA) to resolve multiple, potentially overlapping aspects of transcriptional heterogeneity by testing gene sets for coordinated variability among measured cells.

Published
2016

30. Comparative analysis of metazoan chromatin organization

Author

Ho, Joshua WK, Jung, Youngsook L, Liu, Tao, Alver, Burak H, Lee, Soohyun, Ikegami, Kohta, Sohn, Kyung-Ah, Minoda, Aki, Tolstorukov, Michael Y, Appert, Alex, Parker, Stephen CJ, Gu, Tingting, Kundaje, Anshul, Riddle, Nicole C, Bishop, Eric, Egelhofer, Thea A, Hu, Sheng'en Shawn, Alekseyenko, Artyom A, Rechtsteiner, Andreas, Asker, Dalal, Belsky, Jason A, Bowman, Sarah K, Chen, Q Brent, Chen, Ron A-J, Day, Daniel S, Dong, Yan, Dose, Andrea C, Duan, Xikun, Epstein, Charles B, Ercan, Sevinc, Feingold, Elise A, Ferrari, Francesco, Garrigues, Jacob M, Gehlenborg, Nils, Good, Peter J, Haseley, Psalm, He, Daniel, Herrmann, Moritz, Hoffman, Michael M, Jeffers, Tess E, Kharchenko, Peter V, Kolasinska-Zwierz, Paulina, Kotwaliwale, Chitra V, Kumar, Nischay, Langley, Sasha A, Larschan, Erica N, Latorre, Isabel, Libbrecht, Maxwell W, Lin, Xueqiu, Park, Richard, Pazin, Michael J, Pham, Hoang N, Plachetka, Annette, Qin, Bo, Schwartz, Yuri B, Shoresh, Noam, Stempor, Przemyslaw, Vielle, Anne, Wang, Chengyang, Whittle, Christina M, Xue, Huiling, Kingston, Robert E, Kim, Ju Han, Bernstein, Bradley E, Dernburg, Abby F, Pirrotta, Vincenzo, Kuroda, Mitzi I, Noble, William S, Tullius, Thomas D, Kellis, Manolis, MacAlpine, David M, Strome, Susan, Elgin, Sarah CR, Liu, Xiaole Shirley, Lieb, Jason D, Ahringer, Julie, Karpen, Gary H, and Park, Peter J

Subjects
Biochemistry and Cell Biology, Biological Sciences, Immunization, Human Genome, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Animals, Caenorhabditis elegans, Cell Line, Centromere, Chromatin, Chromatin Assembly and Disassembly, DNA Replication, Drosophila melanogaster, Enhancer Elements, Genetic, Epigenesis, Genetic, Heterochromatin, Histones, Humans, Molecular Sequence Annotation, Nuclear Lamina, Nucleosomes, Promoter Regions, Genetic, Species Specificity, General Science & Technology
Abstract

Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.

Published
2014

31. Author Correction: Comparative cellular analysis of motor cortex in human, marmoset and mouse

Author

Bakken, Trygve E., Jorstad, Nikolas L., Hu, Qiwen, Lake, Blue B., Tian, Wei, Kalmbach, Brian E., Crow, Megan, Hodge, Rebecca D., Krienen, Fenna M., Sorensen, Staci A., Eggermont, Jeroen, Yao, Zizhen, Aevermann, Brian D., Aldridge, Andrew I., Bartlett, Anna, Bertagnolli, Darren, Casper, Tamara, Castanon, Rosa G., Crichton, Kirsten, Daigle, Tanya L., Dalley, Rachel, Dee, Nick, Dembrow, Nikolai, Diep, Dinh, Ding, Song-Lin, Dong, Weixiu, Fang, Rongxin, Fischer, Stephan, Goldman, Melissa, Goldy, Jeff, Graybuck, Lucas T., Herb, Brian R., Hou, Xiaomeng, Kancherla, Jayaram, Kroll, Matthew, Lathia, Kanan, van Lew, Baldur, Li, Yang Eric, Liu, Christine S., Liu, Hanqing, Lucero, Jacinta D., Mahurkar, Anup, McMillen, Delissa, Miller, Jeremy A., Moussa, Marmar, Nery, Joseph R., Nicovich, Philip R., Niu, Sheng-Yong, Orvis, Joshua, Osteen, Julia K., Owen, Scott, Palmer, Carter R., Pham, Thanh, Plongthongkum, Nongluk, Poirion, Olivier, Reed, Nora M., Rimorin, Christine, Rivkin, Angeline, Romanow, William J., Sedeño-Cortés, Adriana E., Siletti, Kimberly, Somasundaram, Saroja, Sulc, Josef, Tieu, Michael, Torkelson, Amy, Tung, Herman, Wang, Xinxin, Xie, Fangming, Yanny, Anna Marie, Zhang, Renee, Ament, Seth A., Behrens, M. Margarita, Bravo, Hector Corrada, Chun, Jerold, Dobin, Alexander, Gillis, Jesse, Hertzano, Ronna, Hof, Patrick R., Höllt, Thomas, Horwitz, Gregory D., Keene, C. Dirk, Kharchenko, Peter V., Ko, Andrew L., Lelieveldt, Boudewijn P., Luo, Chongyuan, Mukamel, Eran A., Pinto-Duarte, António, Preiss, Sebastian, Regev, Aviv, Ren, Bing, Scheuermann, Richard H., Smith, Kimberly, Spain, William J., White, Owen R., Koch, Christof, Hawrylycz, Michael, Tasic, Bosiljka, Macosko, Evan Z., McCarroll, Steven A., Ting, Jonathan T., Zeng, Hongkui, Zhang, Kun, Feng, Guoping, Ecker, Joseph R., Linnarsson, Sten, and Lein, Ed S.

Published
2022
Full Text
View/download PDF

34. Enrichment of HP1a on Drosophila chromosome 4 genes creates an alternate chromatin structure critical for regulation in this heterochromatic domain.

Author

Riddle, Nicole C, Jung, Youngsook L, Gu, Tingting, Alekseyenko, Artyom A, Asker, Dalal, Gui, Hongxing, Kharchenko, Peter V, Minoda, Aki, Plachetka, Annette, Schwartz, Yuri B, Tolstorukov, Michael Y, Kuroda, Mitzi I, Pirrotta, Vincenzo, Karpen, Gary H, Park, Peter J, and Elgin, Sarah CR

Subjects
Chromosomes, Euchromatin, Heterochromatin, Animals, Animals, Genetically Modified, Humans, Drosophila melanogaster, Histone-Lysine N-Methyltransferase, DNA-Directed RNA Polymerases, Drosophila Proteins, Chromosomal Proteins, Non-Histone, Histones, Gene Expression Regulation, Methylation, Mutation, Genetically Modified, Chromosomal Proteins, Non-Histone, Genetics, Developmental Biology
Abstract

Chromatin environments differ greatly within a eukaryotic genome, depending on expression state, chromosomal location, and nuclear position. In genomic regions characterized by high repeat content and high gene density, chromatin structure must silence transposable elements but permit expression of embedded genes. We have investigated one such region, chromosome 4 of Drosophila melanogaster. Using chromatin-immunoprecipitation followed by microarray (ChIP-chip) analysis, we examined enrichment patterns of 20 histone modifications and 25 chromosomal proteins in S2 and BG3 cells, as well as the changes in several marks resulting from mutations in key proteins. Active genes on chromosome 4 are distinct from those in euchromatin or pericentric heterochromatin: while there is a depletion of silencing marks at the transcription start sites (TSSs), HP1a and H3K9me3, but not H3K9me2, are enriched strongly over gene bodies. Intriguingly, genes on chromosome 4 are less frequently associated with paused polymerase. However, when the chromatin is altered by depleting HP1a or POF, the RNA pol II enrichment patterns of many chromosome 4 genes shift, showing a significant decrease over gene bodies but not at TSSs, accompanied by lower expression of those genes. Chromosome 4 genes have a low incidence of TRL/GAGA factor binding sites and a low T(m) downstream of the TSS, characteristics that could contribute to a low incidence of RNA polymerase pausing. Our data also indicate that EGG and POF jointly regulate H3K9 methylation and promote HP1a binding over gene bodies, while HP1a targeting and H3K9 methylation are maintained at the repeats by an independent mechanism. The HP1a-enriched, POF-associated chromatin structure over the gene bodies may represent one type of adaptation for genes embedded in repetitive DNA.

Published
2012

35. Sequence-specific targeting of dosage compensation in Drosophila favors an active chromatin context.

Author

Alekseyenko, Artyom A, Ho, Joshua WK, Peng, Shouyong, Gelbart, Marnie, Tolstorukov, Michael Y, Plachetka, Annette, Kharchenko, Peter V, Jung, Youngsook L, Gorchakov, Andrey A, Larschan, Erica, Gu, Tingting, Minoda, Aki, Riddle, Nicole C, Schwartz, Yuri B, Elgin, Sarah CR, Karpen, Gary H, Pirrotta, Vincenzo, Kuroda, Mitzi I, and Park, Peter J

Subjects
X Chromosome, Chromatin, Nucleosomes, Animals, Drosophila melanogaster, Protein-Serine-Threonine Kinases, RNA-Binding Proteins, Drosophila Proteins, Nuclear Proteins, Histones, Transcription Factors, Transcription, Genetic, Gene Expression Regulation, RNA Interference, Base Composition, Binding Sites, Acetylation, Dosage Compensation, Genetic, Male, Genes, X-Linked, Nucleotide Motifs, Transcription, Genetic, Dosage Compensation, Genes, X-Linked, Genetics, Developmental Biology
Abstract

The Drosophila MSL complex mediates dosage compensation by increasing transcription of the single X chromosome in males approximately two-fold. This is accomplished through recognition of the X chromosome and subsequent acetylation of histone H4K16 on X-linked genes. Initial binding to the X is thought to occur at "entry sites" that contain a consensus sequence motif ("MSL recognition element" or MRE). However, this motif is only ∼2 fold enriched on X, and only a fraction of the motifs on X are initially targeted. Here we ask whether chromatin context could distinguish between utilized and non-utilized copies of the motif, by comparing their relative enrichment for histone modifications and chromosomal proteins mapped in the modENCODE project. Through a comparative analysis of the chromatin features in male S2 cells (which contain MSL complex) and female Kc cells (which lack the complex), we find that the presence of active chromatin modifications, together with an elevated local GC content in the surrounding sequences, has strong predictive value for functional MSL entry sites, independent of MSL binding. We tested these sites for function in Kc cells by RNAi knockdown of Sxl, resulting in induction of MSL complex. We show that ectopic MSL expression in Kc cells leads to H4K16 acetylation around these sites and a relative increase in X chromosome transcription. Collectively, our results support a model in which a pre-existing active chromatin environment, coincident with H3K36me3, contributes to MSL entry site selection. The consequences of MSL targeting of the male X chromosome include increase in nucleosome lability, enrichment for H4K16 acetylation and JIL-1 kinase, and depletion of linker histone H1 on active X-linked genes. Our analysis can serve as a model for identifying chromatin and local sequence features that may contribute to selection of functional protein binding sites in the genome.

Published
2012

36. Comprehensive analysis of the chromatin landscape in Drosophila melanogaster

Author

Kharchenko, Peter V, Alekseyenko, Artyom A, Schwartz, Yuri B, Minoda, Aki, Riddle, Nicole C, Ernst, Jason, Sabo, Peter J, Larschan, Erica, Gorchakov, Andrey A, Gu, Tingting, Linder-Basso, Daniela, Plachetka, Annette, Shanower, Gregory, Tolstorukov, Michael Y, Luquette, Lovelace J, Xi, Ruibin, Jung, Youngsook L, Park, Richard W, Bishop, Eric P, Canfield, Theresa K, Sandstrom, Richard, Thurman, Robert E, MacAlpine, David M, Stamatoyannopoulos, John A, Kellis, Manolis, Elgin, Sarah CR, Kuroda, Mitzi I, Pirrotta, Vincenzo, Karpen, Gary H, and Park, Peter J

Subjects
Biotechnology, Human Genome, Genetics, Prevention, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Cell Line, Chromatin, Chromatin Immunoprecipitation, Chromosomal Proteins, Non-Histone, Deoxyribonuclease I, Drosophila Proteins, Drosophila melanogaster, Exons, Gene Expression Regulation, Genes, Insect, Genome, Insect, Histones, Male, Molecular Sequence Annotation, Oligonucleotide Array Sequence Analysis, Polycomb Repressive Complex 1, RNA, Sequence Analysis, Transcription, Genetic, General Science & Technology
Abstract

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.

Published
2011

37. An assessment of histone-modification antibody quality

Author

Egelhofer, Thea A, Minoda, Aki, Klugman, Sarit, Lee, Kyungjoon, Kolasinska-Zwierz, Paulina, Alekseyenko, Artyom A, Cheung, Ming-Sin, Day, Daniel S, Gadel, Sarah, Gorchakov, Andrey A, Gu, Tingting, Kharchenko, Peter V, Kuan, Samantha, Latorre, Isabel, Linder-Basso, Daniela, Luu, Ying, Ngo, Queminh, Perry, Marc, Rechtsteiner, Andreas, Riddle, Nicole C, Schwartz, Yuri B, Shanower, Gregory A, Vielle, Anne, Ahringer, Julie, Elgin, Sarah CR, Kuroda, Mitzi I, Pirrotta, Vincenzo, Ren, Bing, Strome, Susan, Park, Peter J, Karpen, Gary H, Hawkins, R David, and Lieb, Jason D

Subjects
Biotechnology, Genetics, Generic health relevance, Animals, Antibodies, Antibody Specificity, Blotting, Western, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Chromatin Immunoprecipitation, Drosophila Proteins, Drosophila melanogaster, Histones, Immunoblotting, Protein Processing, Post-Translational, Quality Control, Reproducibility of Results, Chemical Sciences, Biological Sciences, Medical and Health Sciences, Biophysics, Developmental Biology
Abstract

We have tested the specificity and utility of more than 200 antibodies raised against 57 different histone modifications in Drosophila melanogaster, Caenorhabditis elegans and human cells. Although most antibodies performed well, more than 25% failed specificity tests by dot blot or western blot. Among specific antibodies, more than 20% failed in chromatin immunoprecipitation experiments. We advise rigorous testing of histone-modification antibodies before use, and we provide a website for posting new test results (http://compbio.med.harvard.edu/antibodies/).

Published
2011

38. Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla

Author

Furlan, Alessandro, Dyachuk, Vyacheslav, Kastriti, Maria Eleni, Calvo-Enrique, Laura, Abdo, Hind, Hadjab, Saida, Chontorotzea, Tatiana, Akkuratova, Natalia, Usoskin, Dmitry, Kamenev, Dmitry, Petersen, Julian, Sunadome, Kazunori, Memic, Fatima, Marklund, Ulrika, Fried, Kaj, Topilko, Piotr, Lallemend, Francois, Kharchenko, Peter V., Ernfors, Patrik, and Adameyko, Igor

Published
2017

43. RNA velocity of single cells

Author

La Manno, Gioele, Soldatov, Ruslan, Zeisel, Amit, Braun, Emelie, Hochgerner, Hannah, Petukhov, Viktor, Lidschreiber, Katja, Kastriti, Maria E., Lönnerberg, Peter, Furlan, Alessandro, Fan, Jean, Borm, Lars E., Liu, Zehua, van Bruggen, David, Guo, Jimin, He, Xiaoling, Barker, Roger, Sundström, Erik, Castelo-Branco, Gonçalo, Cramer, Patrick, Adameyko, Igor, Linnarsson, Sten, and Kharchenko, Peter V.

Published
2018
Full Text
View/download PDF

46. Proximity-Based Differential Single-Cell Analysis of the Niche to Identify Stem/Progenitor Cell Regulators

Author

Silberstein, Lev, Goncalves, Kevin A., Kharchenko, Peter V., Turcotte, Raphael, Kfoury, Youmna, Mercier, Francois, Baryawno, Ninib, Severe, Nicolas, Bachand, Jacqueline, Spencer, Joel A., Papazian, Ani, Lee, Dongjun, Chitteti, Brahmananda Reddy, Srour, Edward F., Hoggatt, Jonathan, Tate, Tiffany, Lo Celso, Cristina, Ono, Noriaki, Nutt, Stephen, Heino, Jyrki, Sipilä, Kalle, Shioda, Toshihiro, Osawa, Masatake, Lin, Charles P., Hu, Guo-fu, and Scadden, David T.

Published
2016
Full Text
View/download PDF

47. Transcription factors LRF and BCL11A independently repress expression of fetal hemoglobin

Author

Masuda, Takeshi, Wang, Xin, Maeda, Manami, Canver, Matthew C., Sher, Falak, Funnell, Alister P. W., Fisher, Chris, Suciu, Maria, Martyn, Gabriella E., Norton, Laura J., Zhu, Catherine, Kurita, Ryo, Nakamura, Yukio, Xu, Jian, Higgs, Douglas R., Crossley, Merlin, Bauer, Daniel E., Orkin, Stuart H., Kharchenko, Peter V., and Maeda, Takahiro

Published
2016

49. Prostate cancer single-cell and spatial transcriptomic data analyses

Author

Hirz, Taghreed, Mei, Shenglin, Sarkar, Hirak, Kfoury, Youmna, Wu, Shulin, Verhoeven, Bronte M, Subtelny, Alexander O, Zlatev, Dimitar V., Wszolek, Matthew W., Salari, Keyan, Murray, Evan, Chen, Fei, Macosko, Evan Z., Wu, Chin-Lee, Scadden, David T, Dahl, Douglas M, Baryawno, Ninib, Saylor, Philip J, Kharchenko, Peter V, and Sykes, David B

Subjects
prostate cancer, spatial transcriptomic, tumor microenvironment, immune suppressive
Abstract

The treatment of low-risk primary prostate cancer entails active surveillance only, while high-risk disease requires multimodal treatment including surgery, radiation therapy, and hormonal therapy. Recurrence and development of metastatic disease remains a clinical problem, without a clear understanding of what drives immune escape and tumor progression. Here, we comprehensively describe the tumor microenvironment of localized prostate cancer in comparison with adjacent normal samples and healthy controls. Single-cell RNA sequencing and high-resolution spatial transcriptomic analyses reveal tumor context dependent changes in gene expression. Our data indicate that an immune suppressive tumor microenvironment associates with suppressive myeloid populations and exhausted T-cells, in addition to high stromal angiogenic activity. We infer cell-to-cell relationships from high throughput ligand-receptor interaction measurements within undissociated tissue sections. Our work thus provides a highly detailed and comprehensive resource of the prostate tumor microenvironment as well as tumor-stromal cell interactions.

Published
2023
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results