Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
Unit of Laboratory Animal Pathology, University of Veterinary Medicine, Vienna, Austria.
EMBO J. 2021 Nov 15;40(22):e108234. doi: 10.15252/embj.2021108234. Epub 2021 Sep 29.
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.
DNA 甲基化是一种基本的表观遗传修饰，在生物过程中很重要。维持甲基转移酶 DNMT1 对于发育过程中的谱系分化至关重要，但它在组织稳态中的功能尚不完全清楚。我们表明，表皮特异性的 DNMT1 缺失严重破坏了表皮结构和稳态，引发了大规模的先天免疫反应和免疫细胞浸润。从机制上讲，角质细胞中的 DNA 低甲基化触发了转座子去抑制、有丝分裂缺陷和微核形成。DNMT1 缺陷角质细胞中 DNA 的释放激活了 cGAS 和 STING 的信号通路，从而引发炎症。我们的研究结果表明，关键表观遗传标记的破坏直接影响免疫和组织稳态，并可能影响我们对自身炎症性疾病和癌症免疫治疗的理解。
