Central control of dynamic gene circuits governs T cell rest and activation

Maya M. Arce, Jennifer M. Umhoefer, Nadia Arang, Sivakanthan Kasinathan, Jacob W. Freimer, Zachary Steinhart, Haolin Shen, Minh T. N. Pham, Mineto Ota, Anika Wadhera, Rama Dajani, Dmytro Dorovskyi, Yan Yi Chen, Qi Liu, Yuan Zhou, Danielle L. Swaney, Kirsten Obernier, Brian R. Shy, Julia Carnevale, Ansuman T. Satpathy, Nevan J. Krogan, Jonathan K. Pritchard and Alexander Marson ()
Additional contact information
Maya M. Arce: Gladstone-UCSF Institute of Genomic Immunology
Jennifer M. Umhoefer: Gladstone-UCSF Institute of Genomic Immunology
Nadia Arang: University of California
Sivakanthan Kasinathan: Gladstone-UCSF Institute of Genomic Immunology
Jacob W. Freimer: Gladstone-UCSF Institute of Genomic Immunology
Zachary Steinhart: Gladstone-UCSF Institute of Genomic Immunology
Haolin Shen: University of California
Minh T. N. Pham: Stanford University School of Medicine
Mineto Ota: Gladstone-UCSF Institute of Genomic Immunology
Anika Wadhera: Gladstone-UCSF Institute of Genomic Immunology
Rama Dajani: Gladstone-UCSF Institute of Genomic Immunology
Dmytro Dorovskyi: Gladstone-UCSF Institute of Genomic Immunology
Yan Yi Chen: Gladstone-UCSF Institute of Genomic Immunology
Qi Liu: Gladstone-UCSF Institute of Genomic Immunology
Yuan Zhou: University of California
Danielle L. Swaney: University of California
Kirsten Obernier: University of California
Brian R. Shy: Gladstone-UCSF Institute of Genomic Immunology
Julia Carnevale: Gladstone-UCSF Institute of Genomic Immunology
Ansuman T. Satpathy: Gladstone-UCSF Institute of Genomic Immunology
Nevan J. Krogan: University of California
Jonathan K. Pritchard: Stanford University
Alexander Marson: Gladstone-UCSF Institute of Genomic Immunology

Nature, 2025, vol. 637, issue 8047, 930-939

Abstract: Abstract The ability of cells to maintain distinct identities and respond to transient environmental signals requires tightly controlled regulation of gene networks1–3. These dynamic regulatory circuits that respond to extracellular cues in primary human cells remain poorly defined. The need for context-dependent regulation is prominent in T cells, where distinct lineages must respond to diverse signals to mount effective immune responses and maintain homeostasis4–8. Here we performed CRISPR screens in multiple primary human CD4+ T cell contexts to identify regulators that control expression of IL-2Rα, a canonical marker of T cell activation transiently expressed by pro-inflammatory effector T cells and constitutively expressed by anti-inflammatory regulatory T cells where it is required for fitness9–11. Approximately 90% of identified regulators of IL-2Rα had effects that varied across cell types and/or stimulation states, including a subset that even had opposite effects across conditions. Using single-cell transcriptomics after pooled perturbation of context-specific screen hits, we characterized specific factors as regulators of overall rest or activation and constructed state-specific regulatory networks. MED12 — a component of the Mediator complex — serves as a dynamic orchestrator of key regulators, controlling expression of distinct sets of regulators in different T cell contexts. Immunoprecipitation–mass spectrometry revealed that MED12 interacts with the histone methylating COMPASS complex. MED12 was required for histone methylation and expression of genes encoding key context-specific regulators, including the rest maintenance factor KLF2 and the versatile regulator MYC. CRISPR ablation of MED12 blunted the cell-state transitions between rest and activation and protected from activation-induced cell death. Overall, this work leverages CRISPR screens performed across conditions to define dynamic gene circuits required to establish resting and activated T cell states.

Date: 2025
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DOI: 10.1038/s41586-024-08314-y

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