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.

中文翻译：

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DNA 低甲基化导致 cGAS 诱导的表皮自身炎症

DNA 甲基化是一种基本的表观遗传修饰，在整个生物过程中都很重要。维持性甲基转移酶 DNMT1 对于发育过程中的谱系分化至关重要，但其在组织稳态中的功能尚不完全清楚。我们发现表皮特异性 DNMT1 缺失严重破坏了表皮结构和体内平衡，引发了大规模的先天免疫反应和免疫细胞的浸润。从机制上讲，角质形成细胞中的 DNA 低甲基化会引发转座子去抑制、有丝分裂缺陷和微核的形成。DNA 释放到 DNMT1 缺陷的角质形成细胞的细胞质中，通过 cGAS 和 STING 激活信号传导，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。