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  1. Article ; Online: A transcription factor atlas of directed differentiation.

    Joung, Julia / Ma, Sai / Tay, Tristan / Geiger-Schuller, Kathryn R / Kirchgatterer, Paul C / Verdine, Vanessa K / Guo, Baolin / Arias-Garcia, Mario A / Allen, William E / Singh, Ankita / Kuksenko, Olena / Abudayyeh, Omar O / Gootenberg, Jonathan S / Fu, Zhanyan / Macrae, Rhiannon K / Buenrostro, Jason D / Regev, Aviv / Zhang, Feng

    Cell

    2024  

    Language English
    Publishing date 2024-05-01
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2024.04.038
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Systematically characterizing the roles of E3-ligase family members in inflammatory responses with massively parallel Perturb-seq.

    Geiger-Schuller, Kathryn / Eraslan, Basak / Kuksenko, Olena / Dey, Kushal K / Jagadeesh, Karthik A / Thakore, Pratiksha I / Karayel, Ozge / Yung, Andrea R / Rajagopalan, Anugraha / Meireles, Ana M / Yang, Karren Dai / Amir-Zilberstein, Liat / Delorey, Toni / Phillips, Devan / Raychowdhury, Raktima / Moussion, Christine / Price, Alkes L / Hacohen, Nir / Doench, John G /
    Uhler, Caroline / Rozenblatt-Rosen, Orit / Regev, Aviv

    bioRxiv : the preprint server for biology

    2023  

    Abstract: E3 ligases regulate key processes, but many of their roles remain unknown. Using Perturb-seq, we interrogated the function of 1,130 E3 ligases, partners and substrates in the inflammatory response in primary dendritic cells (DCs). Dozens impacted the ... ...

    Abstract E3 ligases regulate key processes, but many of their roles remain unknown. Using Perturb-seq, we interrogated the function of 1,130 E3 ligases, partners and substrates in the inflammatory response in primary dendritic cells (DCs). Dozens impacted the balance of DC1, DC2, migratory DC and macrophage states and a gradient of DC maturation. Family members grouped into co-functional modules that were enriched for physical interactions and impacted specific programs through substrate transcription factors. E3s and their adaptors co-regulated the same processes, but partnered with different substrate recognition adaptors to impact distinct aspects of the DC life cycle. Genetic interactions were more prevalent within than between modules, and a deep learning model, comβVAE, predicts the outcome of new combinations by leveraging modularity. The E3 regulatory network was associated with heritable variation and aberrant gene expression in immune cells in human inflammatory diseases. Our study provides a general approach to dissect gene function.
    Language English
    Publishing date 2023-01-24
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.01.23.525198
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A transcription factor atlas of directed differentiation.

    Joung, Julia / Ma, Sai / Tay, Tristan / Geiger-Schuller, Kathryn R / Kirchgatterer, Paul C / Verdine, Vanessa K / Guo, Baolin / Arias-Garcia, Mario A / Allen, William E / Singh, Ankita / Kuksenko, Olena / Abudayyeh, Omar O / Gootenberg, Jonathan S / Fu, Zhanyan / Macrae, Rhiannon K / Buenrostro, Jason D / Regev, Aviv / Zhang, Feng

    Cell

    2023  Volume 186, Issue 1, Page(s) 209–229.e26

    Abstract: Transcription factors (TFs) regulate gene programs, thereby controlling diverse cellular processes and cell states. To comprehensively understand TFs and the programs they control, we created a barcoded library of all annotated human TF splice isoforms (> ...

    Abstract Transcription factors (TFs) regulate gene programs, thereby controlling diverse cellular processes and cell states. To comprehensively understand TFs and the programs they control, we created a barcoded library of all annotated human TF splice isoforms (>3,500) and applied it to build a TF Atlas charting expression profiles of human embryonic stem cells (hESCs) overexpressing each TF at single-cell resolution. We mapped TF-induced expression profiles to reference cell types and validated candidate TFs for generation of diverse cell types, spanning all three germ layers and trophoblasts. Targeted screens with subsets of the library allowed us to create a tailored cellular disease model and integrate mRNA expression and chromatin accessibility data to identify downstream regulators. Finally, we characterized the effects of combinatorial TF overexpression by developing and validating a strategy for predicting combinations of TFs that produce target expression profiles matching reference cell types to accelerate cellular engineering efforts.
    MeSH term(s) Humans ; Cell Differentiation ; Chromatin ; Gene Expression Regulation ; Human Embryonic Stem Cells/metabolism ; Transcription Factors/metabolism ; Atlases as Topic
    Chemical Substances Chromatin ; Transcription Factors
    Language English
    Publishing date 2023-01-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2022.11.026
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    Zs.A 1167: Show issues Location:
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  4. Article ; Online: The Human and Mouse Enteric Nervous System at Single-Cell Resolution.

    Drokhlyansky, Eugene / Smillie, Christopher S / Van Wittenberghe, Nicholas / Ericsson, Maria / Griffin, Gabriel K / Eraslan, Gokcen / Dionne, Danielle / Cuoco, Michael S / Goder-Reiser, Max N / Sharova, Tatyana / Kuksenko, Olena / Aguirre, Andrew J / Boland, Genevieve M / Graham, Daniel / Rozenblatt-Rosen, Orit / Xavier, Ramnik J / Regev, Aviv

    Cell

    2020  Volume 182, Issue 6, Page(s) 1606–1622.e23

    Abstract: The enteric nervous system (ENS) coordinates diverse functions in the intestine but has eluded comprehensive molecular characterization because of the rarity and diversity of cells. Here we develop two methods to profile the ENS of adult mice and humans ... ...

    Abstract The enteric nervous system (ENS) coordinates diverse functions in the intestine but has eluded comprehensive molecular characterization because of the rarity and diversity of cells. Here we develop two methods to profile the ENS of adult mice and humans at single-cell resolution: RAISIN RNA-seq for profiling intact nuclei with ribosome-bound mRNA and MIRACL-seq for label-free enrichment of rare cell types by droplet-based profiling. The 1,187,535 nuclei in our mouse atlas include 5,068 neurons from the ileum and colon, revealing extraordinary neuron diversity. We highlight circadian expression changes in enteric neurons, show that disease-related genes are dysregulated with aging, and identify differences between the ileum and proximal/distal colon. In humans, we profile 436,202 nuclei, recovering 1,445 neurons, and identify conserved and species-specific transcriptional programs and putative neuro-epithelial, neuro-stromal, and neuro-immune interactions. The human ENS expresses risk genes for neuropathic, inflammatory, and extra-intestinal diseases, suggesting neuronal contributions to disease.
    MeSH term(s) Aging/genetics ; Aging/metabolism ; Animals ; Circadian Clocks/genetics ; Colon/cytology ; Colon/metabolism ; Endoplasmic Reticulum, Rough/genetics ; Endoplasmic Reticulum, Rough/metabolism ; Endoplasmic Reticulum, Rough/ultrastructure ; Enteric Nervous System/cytology ; Enteric Nervous System/metabolism ; Epithelial Cells/metabolism ; Female ; Gene Expression Regulation, Developmental/genetics ; Genetic Predisposition to Disease/genetics ; Humans ; Ileum/cytology ; Ileum/metabolism ; Inflammation/genetics ; Inflammation/metabolism ; Intestinal Diseases/genetics ; Intestinal Diseases/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microscopy, Electron, Transmission ; Nervous System Diseases/genetics ; Nervous System Diseases/metabolism ; Neuroglia/cytology ; Neuroglia/metabolism ; Neurons/cytology ; Neurons/metabolism ; Nissl Bodies/genetics ; Nissl Bodies/metabolism ; Nissl Bodies/ultrastructure ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA-Seq ; Ribosomes/metabolism ; Ribosomes/ultrastructure ; Single-Cell Analysis/methods ; Stromal Cells/metabolism
    Chemical Substances RNA, Messenger
    Language English
    Publishing date 2020-09-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2020.08.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Single-nucleus cross-tissue molecular reference maps toward understanding disease gene function.

    Eraslan, Gökcen / Drokhlyansky, Eugene / Anand, Shankara / Fiskin, Evgenij / Subramanian, Ayshwarya / Slyper, Michal / Wang, Jiali / Van Wittenberghe, Nicholas / Rouhana, John M / Waldman, Julia / Ashenberg, Orr / Lek, Monkol / Dionne, Danielle / Win, Thet Su / Cuoco, Michael S / Kuksenko, Olena / Tsankov, Alexander M / Branton, Philip A / Marshall, Jamie L /
    Greka, Anna / Getz, Gad / Segrè, Ayellet V / Aguet, François / Rozenblatt-Rosen, Orit / Ardlie, Kristin G / Regev, Aviv

    Science (New York, N.Y.)

    2022  Volume 376, Issue 6594, Page(s) eabl4290

    Abstract: Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen ... ...

    Abstract Understanding gene function and regulation in homeostasis and disease requires knowledge of the cellular and tissue contexts in which genes are expressed. Here, we applied four single-nucleus RNA sequencing methods to eight diverse, archived, frozen tissue types from 16 donors and 25 samples, generating a cross-tissue atlas of 209,126 nuclei profiles, which we integrated across tissues, donors, and laboratory methods with a conditional variational autoencoder. Using the resulting cross-tissue atlas, we highlight shared and tissue-specific features of tissue-resident cell populations; identify cell types that might contribute to neuromuscular, metabolic, and immune components of monogenic diseases and the biological processes involved in their pathology; and determine cell types and gene modules that might underlie disease mechanisms for complex traits analyzed by genome-wide association studies.
    MeSH term(s) Biomarkers ; Cell Nucleus/genetics ; Disease/genetics ; Genome-Wide Association Study ; Humans ; Organ Specificity ; Phenotype ; RNA-Seq/methods
    Chemical Substances Biomarkers
    Language English
    Publishing date 2022-05-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.abl4290
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    Zs.A 27: Show issues Location:
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  6. Article: The Human and Mouse Enteric Nervous System at Single-Cell Resolution

    Drokhlyansky, Eugene / Smillie, Christopher S / Van Wittenberghe, Nicholas / Ericsson, Maria / Griffin, Gabriel K / Eraslan, Gokcen / Dionne, Danielle / Cuoco, Michael S / Goder-Reiser, Max N / Sharova, Tatyana / Kuksenko, Olena / Aguirre, Andrew J / Boland, Genevieve M / Graham, Daniel / Rozenblatt-Rosen, Orit / Xavier, Ramnik J / Regev, Aviv

    Cell. 2020 Sept. 17, v. 182, no. 6

    2020  

    Abstract: The enteric nervous system (ENS) coordinates diverse functions in the intestine but has eluded comprehensive molecular characterization because of the rarity and diversity of cells. Here we develop two methods to profile the ENS of adult mice and humans ... ...

    Abstract The enteric nervous system (ENS) coordinates diverse functions in the intestine but has eluded comprehensive molecular characterization because of the rarity and diversity of cells. Here we develop two methods to profile the ENS of adult mice and humans at single-cell resolution: RAISIN RNA-seq for profiling intact nuclei with ribosome-bound mRNA and MIRACL-seq for label-free enrichment of rare cell types by droplet-based profiling. The 1,187,535 nuclei in our mouse atlas include 5,068 neurons from the ileum and colon, revealing extraordinary neuron diversity. We highlight circadian expression changes in enteric neurons, show that disease-related genes are dysregulated with aging, and identify differences between the ileum and proximal/distal colon. In humans, we profile 436,202 nuclei, recovering 1,445 neurons, and identify conserved and species-specific transcriptional programs and putative neuro-epithelial, neuro-stromal, and neuro-immune interactions. The human ENS expresses risk genes for neuropathic, inflammatory, and extra-intestinal diseases, suggesting neuronal contributions to disease.
    Keywords adults ; colon ; humans ; ileum ; mice ; neurons ; risk ; sequence analysis ; transcription (genetics)
    Language English
    Dates of publication 2020-0917
    Size p. 1606-1622.e23.
    Publishing place Elsevier Inc.
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2020.08.003
    Database NAL-Catalogue (AGRICOLA)

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  7. Article ; Online: Multiplexed single-cell transcriptional response profiling to define cancer vulnerabilities and therapeutic mechanism of action.

    McFarland, James M / Paolella, Brenton R / Warren, Allison / Geiger-Schuller, Kathryn / Shibue, Tsukasa / Rothberg, Michael / Kuksenko, Olena / Colgan, William N / Jones, Andrew / Chambers, Emily / Dionne, Danielle / Bender, Samantha / Wolpin, Brian M / Ghandi, Mahmoud / Tirosh, Itay / Rozenblatt-Rosen, Orit / Roth, Jennifer A / Golub, Todd R / Regev, Aviv /
    Aguirre, Andrew J / Vazquez, Francisca / Tsherniak, Aviad

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 4296

    Abstract: Assays to study cancer cell responses to pharmacologic or genetic perturbations are typically restricted to using simple phenotypic readouts such as proliferation rate. Information-rich assays, such as gene-expression profiling, have generally not ... ...

    Abstract Assays to study cancer cell responses to pharmacologic or genetic perturbations are typically restricted to using simple phenotypic readouts such as proliferation rate. Information-rich assays, such as gene-expression profiling, have generally not permitted efficient profiling of a given perturbation across multiple cellular contexts. Here, we develop MIX-Seq, a method for multiplexed transcriptional profiling of post-perturbation responses across a mixture of samples with single-cell resolution, using SNP-based computational demultiplexing of single-cell RNA-sequencing data. We show that MIX-Seq can be used to profile responses to chemical or genetic perturbations across pools of 100 or more cancer cell lines. We combine it with Cell Hashing to further multiplex additional experimental conditions, such as post-treatment time points or drug doses. Analyzing the high-content readout of scRNA-seq reveals both shared and context-specific transcriptional response components that can identify drug mechanism of action and enable prediction of long-term cell viability from short-term transcriptional responses to treatment.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Base Sequence ; Cell Line, Tumor ; Cell Survival/genetics ; Gene Expression Profiling/methods ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Models, Statistical ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Polymorphism, Single Nucleotide ; Pyridones/pharmacology ; Pyrimidinones/pharmacology ; Single-Cell Analysis/methods
    Chemical Substances Antineoplastic Agents ; Pyridones ; Pyrimidinones ; trametinib (33E86K87QN)
    Language English
    Publishing date 2020-08-27
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-17440-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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