DNA hypomethylation leads to cGAS-induced autoinflammation in the epidermis

被引：19

作者：

Beck, Mirjam A. ^{[1
]}

Fischer, Heinz ^{[1
]}

Grabner, Lisa M. ^{[1
]}

Groffics, Tamara ^{[1
,16
]}

Winter, Mircea ^{[1
]}

Tangermann, Simone ^{[2
]}

Meischel, Tina ^{[1
,17
]}

Zaussinger-Haas, Barbara ^{[1
]}

Wagner, Patrick ^{[1
]}

Fischer, Carina ^{[1
]}

Folie, Christina ^{[1
,3
]}

Arand, Julia ^{[1
]}

Schoefer, Christian ^{[1
]}

Ramsahoye, Bernard ^{[4
]}

Lagger, Sabine ^{[2
]}

Machat, Georg ^{[1
]}

Eisenwort, Gregor ^{[5
,18
]}

Schneider, Stephanie ^{[1
,19
]}

Podhornik, Alexandra ^{[1
]}

Kothmayer, Michael ^{[1
]}

Reichart, Ursula ^{[6
]}

Gloesmann, Martin ^{[6
]}

Tamir, Ido ^{[7
]}

Mildner, Michael ^{[8
]}

Sheibani-Tezerji, Raheleh ^{[9
]}

Kenner, Lukas ^{[2
,10
,11
,12
]}

Petzelbauer, Peter ^{[13
]}

Egger, Gerda ^{[9
,11
]}

Sibilia, Maria ^{[14
]}

Ablasser, Andrea ^{[15
]}

Seiser, Christian ^{[1
]}

机构：

[1] Med Univ Vienna, Ctr Anat & Cell Biol, Div Cell & Dev Biol, Vienna, Austria

[2] Univ Vet Med, Unit Lab Anim Pathol, Vienna, Austria

[3] Spinal Cord Injury & Tissue Regenerat Ctr Salzbur, Salzburg, Austria

[4] Univ Edinburgh, Ctr Genom & Expt Med, MRC Inst Genet & Mol Med, Edinburgh, Midlothian, Scotland

[5] Med Univ Vienna, Inst Immunol, Vienna, Austria

[6] Univ Vet Med Vienna, VetCORE Facil Res, Vienna, Austria

[7] Campus Sci Support Facil GmbH, Vienna, Austria

[8] Med Univ Vienna, Res Div Biol & Pathobiol Skin, Vienna, Austria

[9] Ludwig Boltzmann Inst Appl Diagnost, Vienna, Austria

[10] Christian Doppler Lab Appl Metabol, Vienna, Austria

[11] Med Univ Vienna, Dept Pathol, Vienna, Austria

[12] CBmed GmbH, Ctr Biomarker Res Med, Graz, Austria

[13] Med Univ Vienna, Dept Dermatol, Skin & Endothelium Res Div, Vienna, Austria

[14] Med Univ Vienna, Comprehens Canc Ctr, Inst Canc Res, Dept Med 1, Vienna, Austria

[15] Swiss Fed Inst Technol Lausanne EPFL, Global Hlth Inst, Lausanne, Switzerland

[16] Vienna BioCtr, Max Perutz Labs, Vienna, Austria

[17] Univ Melbourne, Dept Microbiol & Immunol, Peter Doherty Inst Infect & Immun, Melbourne, Vic, Australia

[18] Med Univ Vienna, Dept Hematol & Hemostaseol, Clin Internal Med 1, Vienna, Austria

[19] Ludwig Maximilians Univ Munchen, Gene Ctr, Max von Pettenkofer Inst Virol, Munich, Germany

来源：

EMBO JOURNAL | 2021年 / 40卷 / 22期

基金：

奥地利科学基金会;

关键词：

autoinflammation; cytosolic DNA; DNA methylation; epigenetics; innate immune system; METHYLATION CAUSES; STING PATHWAY; STEM-CELLS; CANCER; DNMT1; SELF; SKIN; EXPRESSION; ROLES; INFLAMMATION;

D O I：

10.15252/embj.2021108234

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：18

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