DNA hypomethylation leads to cGAS‐induced autoinflammation in the epidermis
| Autor: | Bernard Ramsahoye, Christina Folie, Sabine Lagger, Raheleh Sheibani-Tezerji, Alexandra Podhornik, Julia Arand, Gerda Egger, Peter Petzelbauer, Gregor Eisenwort, Tina Meischel, Andrea Ablasser, Martin Glösmann, Ursula Reichart, Ido Tamir, Maria Sibilia, Heinz Fischer, Georg Machat, Michael Mildner, Lisa M. Grabner, Barbara Zaussinger-Haas, Lukas Kenner, Simone Tangermann, Stephanie Schneider, Mircea Winter, Christian Schöfer, Patrick Wagner, Michael Kothmayer, Mirjam A Beck, Tamara Groffics, Carina Fischer, Christian Seiser |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
DNA (Cytosine-5-)-Methyltransferase 1
Keratinocytes Methyltransferase Interferon-Induced Helicase IFIH1 Immunology innate immune system Dermatitis Mice Transgenic Biology cytosolic DNA General Biochemistry Genetics and Molecular Biology Article Immune system Cytosol Animals Humans Epigenetics Molecular Biology Tissue homeostasis Adaptor Proteins Signal Transducing Chromosome Aberrations Innate immune system DNA methylation General Immunology and Microbiology epigenetics General Neuroscience Membrane Proteins Articles autoinflammation Nucleotidyltransferases Immunity Innate Cell biology Chromatin Transcription & Genomics DNMT1 Epidermis DNA hypomethylation |
| Zdroj: | The EMBO Journal |
| ISSN: | 1460-2075 0261-4189 |
| Popis: | DNA methylation is a fundamental epigenetic modification, important across biological processes. The maintenance methyltransferase DNMT1 is essential for lineage differentiation during development, but its functions in tissue homeostasis are incompletely understood. We show that epidermis‐specific DNMT1 deletion severely disrupts epidermal structure and homeostasis, initiating a massive innate immune response and infiltration of immune cells. Mechanistically, DNA hypomethylation in keratinocytes triggered transposon derepression, mitotic defects, and formation of micronuclei. DNA release into the cytosol of DNMT1‐deficient keratinocytes activated signaling through cGAS and STING, thus triggering inflammation. Our findings show that disruption of a key epigenetic mark directly impacts immune and tissue homeostasis, and potentially impacts our understanding of autoinflammatory diseases and cancer immunotherapy. Deletion of maintenance methyltransferase DNMT1 in keratinocytes causes formation of micronuclei, whose rupture and cytosolic DNA release activates inflammatory signalling via cGAS/STING. |
| Databáze: | OpenAIRE |
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