Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function
| Autor: | Luisa Morales-Nebreda, Manuel A. Torres Acosta, Shang Yang Chen, Mahzad Akbarpour, Elizabeth M. Steinert, Kishore R. Anekalla, Hiam Abdala-Valencia, Paul Cheresh, Yuliya Politanska, Samuel E. Weinberg, Kathryn A. Helmin, Benjamin D. Singer |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Lineage (genetic) Regulatory T cell T cell Ubiquitin-Protein Ligases Population chemical and pharmacologic phenomena Mice Transgenic Biology T-Lymphocytes Regulatory 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Epigenetics education 030304 developmental biology 0303 health sciences education.field_of_study FOXP3 hemic and immune systems Forkhead Transcription Factors General Medicine Methylation DNA Methylation Cell biology 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis DNA methylation CCAAT-Enhancer-Binding Proteins 030215 immunology DNA hypomethylation Research Article |
| Zdroj: | J Clin Invest |
| Popis: | Regulatory T (Treg) cells require Foxp3 expression and induction of a specific DNA hypomethylation signature during development, after which Treg cells persist as a self-renewing population that regulates immune system activation. Whether maintenance DNA methylation is required for Treg cell lineage development and stability and how methylation patterns are maintained during lineage self-renewal remain unclear. Here, we demonstrate that the epigenetic regulator Uhrf1 is essential for maintenance of methyl-DNA marks that stabilize Treg cellular identity by repressing effector T cell transcriptional programs. Constitutive and induced deficiency of Uhrf1 within Foxp3+ cells resulted in global yet non-uniform loss of DNA methylation, derepression of inflammatory transcriptional programs, destabilization of the Treg cell lineage, spontaneous inflammation, and enhanced tumor immunity. These findings support a paradigm in which maintenance DNA methylation is required in distinct regions of the Treg cell genome for both lineage establishment and stability of identity and suppressive function. |
| Databáze: | OpenAIRE |
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