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Integrated single-cell profiling dissects cell-state-specific enhancer landscapes of human tumor-infiltrating CD8+ T cells

Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify gene-regulatory landscapes in a wide bre...

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Hauptverfasser: Riegel, Dania (VerfasserIn) , Romero-Fernández, Elena (VerfasserIn) , Simon, Malte (VerfasserIn) , Adenugba, Akinbami Raphael (VerfasserIn) , Singer, Katrin (VerfasserIn) , Mayr, Roman (VerfasserIn) , Weber, Florian (VerfasserIn) , Kleemann, Mark (VerfasserIn) , Imbusch, Charles (VerfasserIn) , Kreutz, Marina (VerfasserIn) , Brors, Benedikt (VerfasserIn) , Ugele, Ines (VerfasserIn) , Werner, Jens M. (VerfasserIn) , Siska, Peter J. (VerfasserIn) , Schmidl, Christian (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 16 February 2023
In: Molecular cell
Year: 2023, Jahrgang: 83, Heft: 4, Pages: 622-636.e10
ISSN:1097-4164
DOI:10.1016/j.molcel.2022.12.029
Online-Zugang:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.molcel.2022.12.029
Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S1097276522012126
Volltext
Verfasserangaben:Dania Riegel, Elena Romero-Fernández, Malte Simon, Akinbami Raphael Adenugba, Katrin Singer, Roman Mayr, Florian Weber, Mark Kleemann, Charles D. Imbusch, Marina Kreutz, Benedikt Brors, Ines Ugele, Jens M. Werner, Peter J. Siska, and Christian Schmidl
Beschreibung
Zusammenfassung:Despite extensive studies on the chromatin landscape of exhausted T cells, the transcriptional wiring underlying the heterogeneous functional and dysfunctional states of human tumor-infiltrating lymphocytes (TILs) is incompletely understood. Here, we identify gene-regulatory landscapes in a wide breadth of functional and dysfunctional CD8+ TIL states covering four cancer entities using single-cell chromatin profiling. We map enhancer-promoter interactions in human TILs by integrating single-cell chromatin accessibility with single-cell RNA-seq data from tumor-entity-matching samples and prioritize cell-state-specific genes by super-enhancer analysis. Besides revealing entity-specific chromatin remodeling in exhausted TILs, our analyses identify a common chromatin trajectory to TIL dysfunction and determine key enhancers, transcriptional regulators, and deregulated genes involved in this process. Finally, we validate enhancer regulation at immunotherapeutically relevant loci by targeting non-coding regulatory elements with potent CRISPR activators and repressors. In summary, our study provides a framework for understanding and manipulating cell-state-specific gene-regulatory cues from human tumor-infiltrating lymphocytes.
Beschreibung:Online verfügbar 18. Januar 2023, Artikelversion 16. Februar 2023
Gesehen am 29.03.2023
Im Titel ist das Pluszeichen hochgestellt
Beschreibung:Online Resource
ISSN:1097-4164
DOI:10.1016/j.molcel.2022.12.029

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