Dataset Information

DNA hypomethylation leads to cGAS-induced autoinflammation in the epidermis.

ABSTRACT: 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.

SUBMITTER: Beck MA

PROVIDER: S-EPMC8591534 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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DNA hypomethylation leads to cGAS-induced autoinflammation in the epidermis.

Beck Mirjam A MA Fischer Heinz H Grabner Lisa M LM Groffics Tamara T Winter Mircea M Tangermann Simone S Meischel Tina T Zaussinger-Haas Barbara B Wagner Patrick P Fischer Carina C Folie Christina C Arand Julia J Schöfer Christian C Ramsahoye Bernard B Lagger Sabine S Machat Georg G Eisenwort Gregor G Schneider Stephanie S Podhornik Alexandra A Kothmayer Michael M Reichart Ursula U Glösmann Martin M Tamir Ido I Mildner Michael M Sheibani-Tezerji Raheleh R Kenner Lukas L Petzelbauer Peter P Egger Gerda G Sibilia Maria M Ablasser Andrea A Seiser Christian C

The EMBO journal 20210929 22

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 ...[more]

PMID: 34586646

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Project description:Genomic hypomethylation is a consistent finding in both human and animal tumors and mounting experimental evidence suggests a key role for epigenetic events in tumorigenesis. Furthermore, it has been suggested that early changes in DNA methylation and histone modifications may serve as sensitive predictive markers in animal testing for carcinogenic potency of environmental agents. Alterations in metabolism of methyl donors, disturbances in activity and/or expression of DNA methyltransferases, and presence of DNA single-strand breaks could contribute to the loss of cytosine methylation during carcinogenesis; however, the precise mechanisms of genomic hypomethylation induced by chemical carcinogens remain largely unknown. This study examined the mechanism of DNA hypomethylation during hepatocarcinogenesis induced by peroxisome proliferators WY-14,643 (4-chloro-6-(2,3-xylidino)-pyrimidynylthioacetic acid) and DEHP (di-(2-ethylhexyl)phthalate), agents acting through non-genotoxic mode of action. In the liver of male Fisher 344 rats exposed to WY-14,643 (0.1% (w/w), 5 months), the level of genomic hypomethylation increased by approximately 2-fold, as compared to age-matched controls, while in the DEHP group (1.2% (w/w), 5 months) DNA methylation did not change. Global DNA hypomethylation in livers from WY-14,643 group was accompanied by the accumulation of DNA single-strand breaks, increased cell proliferation, and diminished expression of DNA methyltransferase 1, while the metabolism of methyl donors was not affected. In contrast, none of these parameters changed significantly in rats fed DEHP. Since WY-14,643 is much more potent carcinogen than DEHP, we conclude that the extent of loss of DNA methylation may be related to the carcinogenic potential of the chemical agent, and that accumulation of DNA single-strand breaks coupled to the increase in cell proliferation and altered DNA methyltransferase expression may explain genomic hypomethylation during peroxisome proliferator-induced carcinogenesis.

Dataset Information

DNA hypomethylation leads to cGAS-induced autoinflammation in the epidermis.

Publications

DNA hypomethylation leads to cGAS-induced autoinflammation in the epidermis.

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