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  1. Artikel ; Online: The genetic basis of autoimmunity seen through the lens of T cell functional traits.

    Lagattuta, Kaitlyn A / Park, Hannah L / Rumker, Laurie / Ishigaki, Kazuyoshi / Nathan, Aparna / Raychaudhuri, Soumya

    Nature communications

    2024  Band 15, Heft 1, Seite(n) 1204

    Abstract: Autoimmune disease heritability is enriched in T cell-specific regulatory regions of the genome. Modern-day T cell datasets now enable association studies between single nucleotide polymorphisms (SNPs) and a myriad of molecular phenotypes, including ... ...

    Abstract Autoimmune disease heritability is enriched in T cell-specific regulatory regions of the genome. Modern-day T cell datasets now enable association studies between single nucleotide polymorphisms (SNPs) and a myriad of molecular phenotypes, including chromatin accessibility, gene expression, transcriptional programs, T cell antigen receptor (TCR) amino acid usage, and cell state abundances. Such studies have identified hundreds of quantitative trait loci (QTLs) in T cells that colocalize with genetic risk for autoimmune disease. The key challenge facing immunologists today lies in synthesizing these results toward a unified understanding of the autoimmune T cell: which genes, cell states, and antigens drive tissue destruction?
    Mesh-Begriff(e) Humans ; T-Lymphocytes ; Autoimmunity/genetics ; Quantitative Trait Loci/genetics ; Phenotype ; Polymorphism, Single Nucleotide ; Receptors, Antigen, T-Cell/genetics ; Autoimmune Diseases/genetics ; Genome-Wide Association Study
    Chemische Substanzen Receptors, Antigen, T-Cell
    Sprache Englisch
    Erscheinungsdatum 2024-02-08
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-45170-w
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel: The T cell receptor sequence influences the likelihood of T cell memory formation.

    Lagattuta, Kaitlyn A / Nathan, Aparna / Rumker, Laurie / Birnbaum, Michael E / Raychaudhuri, Soumya

    bioRxiv : the preprint server for biology

    2023  

    Abstract: T cell differentiation depends on activation through the T cell receptor (TCR), whose amino acid sequence varies cell to cell. Particular TCR amino acid sequences nearly guarantee Mucosal-Associated Invariant T (MAIT) and Natural Killer T (NKT) cell ... ...

    Abstract T cell differentiation depends on activation through the T cell receptor (TCR), whose amino acid sequence varies cell to cell. Particular TCR amino acid sequences nearly guarantee Mucosal-Associated Invariant T (MAIT) and Natural Killer T (NKT) cell fates. To comprehensively define how TCR amino acids affects all T cell fates, we analyze the paired αβTCR sequence and transcriptome of 819,772 single cells. We find that hydrophobic CDR3 residues promote regulatory T cell transcriptional states in both the CD8 and CD4 lineages. Most strikingly, we find a set of TCR sequence features, concentrated in CDR2α, that promotes positive selection in the thymus as well as transition from naïve to memory in the periphery. Even among T cells that recognize the same antigen, these TCR sequence features help to explain which T cells form immunological memory, which is essential for effective pathogen response.
    Sprache Englisch
    Erscheinungsdatum 2023-07-23
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2023.07.20.549939
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Single-cell genomics meets human genetics.

    Cuomo, Anna S E / Nathan, Aparna / Raychaudhuri, Soumya / MacArthur, Daniel G / Powell, Joseph E

    Nature reviews. Genetics

    2023  Band 24, Heft 8, Seite(n) 535–549

    Abstract: Single-cell genomic technologies are revealing the cellular composition, identities and states in tissues at unprecedented resolution. They have now scaled to the point that it is possible to query samples at the population level, across thousands of ... ...

    Abstract Single-cell genomic technologies are revealing the cellular composition, identities and states in tissues at unprecedented resolution. They have now scaled to the point that it is possible to query samples at the population level, across thousands of individuals. Combining single-cell information with genotype data at this scale provides opportunities to link genetic variation to the cellular processes underpinning key aspects of human biology and disease. This strategy has potential implications for disease diagnosis, risk prediction and development of therapeutic solutions. But, effectively integrating large-scale single-cell genomic data, genetic variation and additional phenotypic data will require advances in data generation and analysis methods. As single-cell genetics begins to emerge as a field in its own right, we review its current state and the challenges and opportunities ahead.
    Mesh-Begriff(e) Humans ; Genomics/methods ; Genome ; Genotype ; Human Genetics
    Sprache Englisch
    Erscheinungsdatum 2023-04-21
    Erscheinungsland England
    Dokumenttyp Journal Article ; Review
    ZDB-ID 2035157-4
    ISSN 1471-0064 ; 1471-0056
    ISSN (online) 1471-0064
    ISSN 1471-0056
    DOI 10.1038/s41576-023-00599-5
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  4. Artikel ; Online: Methods and Insights from Single-Cell Expression Quantitative Trait Loci.

    Kang, Joyce B / Raveane, Alessandro / Nathan, Aparna / Soranzo, Nicole / Raychaudhuri, Soumya

    Annual review of genomics and human genetics

    2023  Band 24, Seite(n) 277–303

    Abstract: Recent advancements in single-cell technologies have enabled expression quantitative trait locus (eQTL) analysis across many individuals at single-cell resolution. Compared with bulk RNA sequencing, which averages gene expression across cell types and ... ...

    Abstract Recent advancements in single-cell technologies have enabled expression quantitative trait locus (eQTL) analysis across many individuals at single-cell resolution. Compared with bulk RNA sequencing, which averages gene expression across cell types and cell states, single-cell assays capture the transcriptional states of individual cells, including fine-grained, transient, and difficult-to-isolate populations at unprecedented scale and resolution. Single-cell eQTL (sc-eQTL) mapping can identify context-dependent eQTLs that vary with cell states, including some that colocalize with disease variants identified in genome-wide association studies. By uncovering the precise contexts in which these eQTLs act, single-cell approaches can unveil previously hidden regulatory effects and pinpoint important cell states underlying molecular mechanisms of disease. Here, we present an overview of recently deployed experimental designs in sc-eQTL studies. In the process, we consider the influence of study design choices such as cohort, cell states, and ex vivo perturbations. We then discuss current methodologies, modeling approaches, and technical challenges as well as future opportunities and applications.
    Mesh-Begriff(e) Humans ; Quantitative Trait Loci ; Genome-Wide Association Study/methods ; Chromosome Mapping ; Research Design
    Sprache Englisch
    Erscheinungsdatum 2023-05-17
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2037670-4
    ISSN 1545-293X ; 1527-8204
    ISSN (online) 1545-293X
    ISSN 1527-8204
    DOI 10.1146/annurev-genom-101422-100437
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel: Reproducible single cell annotation of programs underlying T-cell subsets, activation states, and functions.

    Kotliar, Dylan / Curtis, Michelle / Agnew, Ryan / Weinand, Kathryn / Nathan, Aparna / Baglaenko, Yuriy / Zhao, Yu / Sabeti, Pardis C / Rao, Deepak A / Raychaudhuri, Soumya

    bioRxiv : the preprint server for biology

    2024  

    Abstract: T-cells recognize antigens and induce specialized gene expression programs (GEPs) enabling functions including proliferation, cytotoxicity, and cytokine production. Traditionally, different classes of helper T-cells express mutually exclusive responses - ...

    Abstract T-cells recognize antigens and induce specialized gene expression programs (GEPs) enabling functions including proliferation, cytotoxicity, and cytokine production. Traditionally, different classes of helper T-cells express mutually exclusive responses - for example, Th1, Th2, and Th17 programs. However, new single-cell RNA sequencing (scRNA-Seq) experiments have revealed a continuum of T-cell states without discrete clusters corresponding to these subsets, implying the need for new analytical frameworks. Here, we advance the characterization of T-cells with T-CellAnnoTator (TCAT), a pipeline that simultaneously quantifies pre-defined GEPs capturing activation states and cellular subsets. From 1,700,000 T-cells from 700 individuals across 38 tissues and five diverse disease contexts, we discover 46 reproducible GEPs reflecting the known core functions of T-cells including proliferation, cytotoxicity, exhaustion, and T helper effector states. We experimentally characterize several novel activation programs and apply TCAT to describe T-cell activation and exhaustion in Covid-19 and cancer, providing insight into T-cell function in these diseases.
    Sprache Englisch
    Erscheinungsdatum 2024-05-05
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2024.05.03.592310
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel: Granzyme K drives a newly-intentified pathway of complement activation.

    Donado, Carlos A / Jonsson, A Helena / Theisen, Erin / Zhang, Fan / Nathan, Aparna / Rupani, Karishma Vijay / Jones, Dominique / Raychaudhuri, Soumya / Dwyer, Daniel F / Brenner, Michael B

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Granzymes are a family of serine proteases mainly expressed by ... ...

    Abstract Granzymes are a family of serine proteases mainly expressed by CD8
    Sprache Englisch
    Erscheinungsdatum 2024-05-26
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2024.05.22.595315
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  7. Artikel ; Online: The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis.

    Weinand, Kathryn / Sakaue, Saori / Nathan, Aparna / Jonsson, Anna Helena / Zhang, Fan / Watts, Gerald F M / Al Suqri, Majd / Zhu, Zhu / Rao, Deepak A / Anolik, Jennifer H / Brenner, Michael B / Donlin, Laura T / Wei, Kevin / Raychaudhuri, Soumya

    Nature communications

    2024  Band 15, Heft 1, Seite(n) 4650

    Abstract: Synovial tissue inflammation is a hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states has ...

    Abstract Synovial tissue inflammation is a hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states has yet to be defined. Here, we examine genome-wide open chromatin at single-cell resolution in 30 synovial tissue samples, including 12 samples with transcriptional data in multimodal experiments. We identify 24 chromatin classes and predict their associated transcription factors, including a CD8 + GZMK+ class associated with EOMES and a lining fibroblast class associated with AP-1. By integrating with an RA tissue transcriptional atlas, we propose that these chromatin classes represent 'superstates' corresponding to multiple transcriptional cell states. Finally, we demonstrate the utility of this RA tissue chromatin atlas through the associations between disease phenotypes and chromatin class abundance, as well as the nomination of classes mediating the effects of putatively causal RA genetic variants.
    Mesh-Begriff(e) Arthritis, Rheumatoid/genetics ; Arthritis, Rheumatoid/metabolism ; Arthritis, Rheumatoid/pathology ; Arthritis, Rheumatoid/immunology ; Humans ; Chromatin/metabolism ; Chromatin/genetics ; Synovial Membrane/metabolism ; Synovial Membrane/pathology ; T-Box Domain Proteins/metabolism ; T-Box Domain Proteins/genetics ; Epigenesis, Genetic ; Single-Cell Analysis ; Transcription Factors/metabolism ; Transcription Factors/genetics ; Fibroblasts/metabolism ; Transcription Factor AP-1/metabolism ; Transcription Factor AP-1/genetics ; Transcription, Genetic ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism
    Chemische Substanzen Chromatin ; T-Box Domain Proteins ; EOMES protein, human ; Transcription Factors ; Transcription Factor AP-1
    Sprache Englisch
    Erscheinungsdatum 2024-05-31
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-024-48620-7
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  8. Artikel ; Online: Immunosuppression causes dynamic changes in expression QTLs in psoriatic skin.

    Xiao, Qian / Mears, Joseph / Nathan, Aparna / Ishigaki, Kazuyoshi / Baglaenko, Yuriy / Lim, Noha / Cooney, Laura A / Harris, Kristina M / Anderson, Mark S / Fox, David A / Smilek, Dawn E / Krueger, James G / Raychaudhuri, Soumya

    Nature communications

    2023  Band 14, Heft 1, Seite(n) 6268

    Abstract: Psoriasis is a chronic, systemic inflammatory condition primarily affecting skin. While the role of the immune compartment (e.g., T cells) is well established, the changes in the skin compartment are more poorly understood. Using longitudinal skin ... ...

    Abstract Psoriasis is a chronic, systemic inflammatory condition primarily affecting skin. While the role of the immune compartment (e.g., T cells) is well established, the changes in the skin compartment are more poorly understood. Using longitudinal skin biopsies (n = 375) from the "Psoriasis Treatment with Abatacept and Ustekinumab: A Study of Efficacy"(PAUSE) clinical trial (n = 101), we report 953 expression quantitative trait loci (eQTLs). Of those, 116 eQTLs have effect sizes that were modulated by local skin inflammation (eQTL interactions). By examining these eQTL genes (eGenes), we find that most are expressed in the skin tissue compartment, and a subset overlap with the NRF2 pathway. Indeed, the strongest eQTL interaction signal - rs1491377616-LCE3C - links a psoriasis risk locus with a gene specifically expressed in the epidermis. This eQTL study highlights the potential to use biospecimens from clinical trials to discover in vivo eQTL interactions with therapeutically relevant environmental variables.
    Mesh-Begriff(e) Humans ; Quantitative Trait Loci/genetics ; Skin/pathology ; Psoriasis/drug therapy ; Psoriasis/genetics ; Psoriasis/pathology ; Immunosuppression Therapy ; Biopsy ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide
    Sprache Englisch
    Erscheinungsdatum 2023-10-07
    Erscheinungsland England
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-41984-2
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  9. Artikel: The Chromatin Landscape of Pathogenic Transcriptional Cell States in Rheumatoid Arthritis.

    Weinand, Kathryn / Sakaue, Saori / Nathan, Aparna / Jonsson, Anna Helena / Zhang, Fan / Watts, Gerald F M / Zhu, Zhu / Rao, Deepak A / Anolik, Jennifer H / Brenner, Michael B / Donlin, Laura T / Wei, Kevin / Raychaudhuri, Soumya

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Synovial tissue inflammation is the hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states ... ...

    Abstract Synovial tissue inflammation is the hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states has yet to be defined. We measured genome-wide open chromatin at single cell resolution from 30 synovial tissue samples, including 12 samples with transcriptional data in multimodal experiments. We identified 24 chromatin classes and predicted their associated transcription factors, including a
    Sprache Englisch
    Erscheinungsdatum 2023-04-08
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2023.04.07.536026
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  10. Artikel ; Online: Dynamic regulatory elements in single-cell multimodal data implicate key immune cell states enriched for autoimmune disease heritability.

    Gupta, Anika / Weinand, Kathryn / Nathan, Aparna / Sakaue, Saori / Zhang, Martin Jinye / Donlin, Laura / Wei, Kevin / Price, Alkes L / Amariuta, Tiffany / Raychaudhuri, Soumya

    Nature genetics

    2023  Band 55, Heft 12, Seite(n) 2200–2210

    Abstract: In autoimmune diseases such as rheumatoid arthritis, the immune system attacks the body's own cells. Developing a precise understanding of the cell states where noncoding autoimmune risk variants impart causal mechanisms is critical to developing ... ...

    Abstract In autoimmune diseases such as rheumatoid arthritis, the immune system attacks the body's own cells. Developing a precise understanding of the cell states where noncoding autoimmune risk variants impart causal mechanisms is critical to developing curative therapies. Here, to identify noncoding regions with accessible chromatin that associate with cell-state-defining gene expression patterns, we leveraged multimodal single-nucleus RNA and assay for transposase-accessible chromatin (ATAC) sequencing data across 28,674 cells from the inflamed synovial tissue of 12 donors. Specifically, we used a multivariate Poisson model to predict peak accessibility from single-nucleus RNA sequencing principal components. For 14 autoimmune diseases, we discovered that cell-state-dependent ('dynamic') chromatin accessibility peaks in immune cell types were enriched for heritability, compared with cell-state-invariant ('cs-invariant') peaks. These dynamic peaks marked regulatory elements associated with T peripheral helper, regulatory T, dendritic and STAT1
    Mesh-Begriff(e) Humans ; Chromatin/genetics ; Regulatory Sequences, Nucleic Acid/genetics ; Chromosomes ; Autoimmune Diseases/genetics ; Genome, Human
    Chemische Substanzen Chromatin
    Sprache Englisch
    Erscheinungsdatum 2023-11-30
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1108734-1
    ISSN 1546-1718 ; 1061-4036
    ISSN (online) 1546-1718
    ISSN 1061-4036
    DOI 10.1038/s41588-023-01577-7
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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