DNA hypomethylation leads to cGAS-induced autoinflammation in the epidermis.
Adaptor Proteins, Signal Transducing
/ metabolism
Animals
Chromosome Aberrations
Cytosol
/ physiology
DNA (Cytosine-5-)-Methyltransferase 1
/ genetics
DNA Methylation
Dermatitis
/ genetics
Epidermis
/ physiopathology
Humans
Immunity, Innate
/ genetics
Interferon-Induced Helicase, IFIH1
/ metabolism
Keratinocytes
/ immunology
Membrane Proteins
/ genetics
Mice, Transgenic
Nucleotidyltransferases
/ genetics
DNA methylation
autoinflammation
cytosolic DNA
epigenetics
innate immune system
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
15 11 2021
15 11 2021
Historique:
revised:
28
08
2021
received:
13
03
2021
accepted:
31
08
2021
pubmed:
30
9
2021
medline:
4
1
2022
entrez:
29
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34586646
doi: 10.15252/embj.2021108234
pmc: PMC8591534
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
IPS-1 protein, mouse
0
Membrane Proteins
0
Sting1 protein, mouse
0
DNA (Cytosine-5-)-Methyltransferase 1
EC 2.1.1.37
Dnmt1 protein, mouse
EC 2.1.1.37
Nucleotidyltransferases
EC 2.7.7.-
cGAS protein, mouse
EC 2.7.7.-
Ifih1 protein, mouse
EC 3.6.1.-
Interferon-Induced Helicase, IFIH1
EC 3.6.4.13
Banques de données
GEO
['GSE166356']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e108234Subventions
Organisme : Austrian Science Fund FWF
ID : P 28034
Pays : Austria
Informations de copyright
© 2021 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Semin Cell Dev Biol. 2010 Apr;21(2):238-46
pubmed: 19892028
Immunol Rev. 2019 Jul;290(1):24-38
pubmed: 31355488
Nat Rev Cancer. 2019 Mar;19(3):151-161
pubmed: 30723290
Nat Immunol. 2020 Jan;21(1):17-29
pubmed: 31819255
Genes Dev. 2013 Feb 15;27(4):372-7
pubmed: 23431054
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
J Mol Biol. 2017 May 19;429(10):1459-1475
pubmed: 28214512
Immunity. 2016 Apr 19;44(4):739-54
pubmed: 27096317
Sci Rep. 2018 Sep 7;8(1):13434
pubmed: 30194332
Nat Immunol. 2016 Jul;17(7):806-15
pubmed: 27240213
Int Rev Cell Mol Biol. 2013;306:1-42
pubmed: 24016522
Oncotarget. 2016 Jan 26;7(4):3726-39
pubmed: 26771138
Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):E5699-705
pubmed: 26371324
Mol Ther. 2021 May 5;29(5):1758-1771
pubmed: 33571681
Genome Biol. 2009;10(3):R25
pubmed: 19261174
Cell. 1992 Jun 12;69(6):915-26
pubmed: 1606615
Front Mol Biosci. 2021 Jun 16;8:627143
pubmed: 34222326
Proc Natl Acad Sci U S A. 2020 Jul 28;117(30):17785-17795
pubmed: 32651270
Nat Rev Immunol. 2016 Sep;16(9):566-80
pubmed: 27455396
Discov Med. 2011 Dec;12(67):535-45
pubmed: 22204770
Nat Rev Immunol. 2019 Jan;19(1):19-30
pubmed: 30429578
Genes Cells. 2006 Jul;11(7):805-14
pubmed: 16824199
J Invest Dermatol. 2012 Mar;132(3 Pt 1):506-8
pubmed: 22327261
PLoS Genet. 2012 Jun;8(6):e1002750
pubmed: 22761581
Methods Mol Biol. 2002;200:17-27
pubmed: 11951652
Semin Cell Dev Biol. 2007 Apr;18(2):225-36
pubmed: 17317239
Genome Biol. 2014;15(12):550
pubmed: 25516281
Cell Rep. 2014 Nov 20;9(4):1482-94
pubmed: 25456137
J Immunol. 2015 Feb 15;194(4):1545-54
pubmed: 25609843
Nat Rev Drug Discov. 2020 Nov;19(11):776-800
pubmed: 32929243
Immunity. 2020 Jul 14;53(1):54-77
pubmed: 32668228
Nat Genet. 2007 Mar;39(3):391-6
pubmed: 17322882
J Exp Med. 2017 Dec 4;214(12):3611-3626
pubmed: 29030458
EMBO J. 2013 Dec 11;32(24):3176-91
pubmed: 24240174
J Invest Dermatol. 2012 Dec;132(12):2681-90
pubmed: 22763785
BMC Genomics. 2014 Jul 11;15:583
pubmed: 25012247
Cell. 2000 Jul 21;102(2):211-20
pubmed: 10943841
Curr Rheumatol Rep. 2020 Jun 16;22(7):32
pubmed: 32548765
Nature. 2018 Jan 25;553(7689):467-472
pubmed: 29342134
Nature. 2017 Aug 24;548(7668):461-465
pubmed: 28738408
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
EMBO J. 2021 Nov 15;40(22):e108234
pubmed: 34586646
Genes Dev. 2008 Apr 15;22(8):976-85
pubmed: 18413712
Nature. 2010 Jan 28;463(7280):563-7
pubmed: 20081831
Nature. 1999 Nov 11;402(6758):187-91
pubmed: 10647011
Oncotarget. 2020 Jul 28;11(30):2930-2955
pubmed: 32774773
Cancer Discov. 2020 Jan;10(1):26-39
pubmed: 31852718
Cell Res. 2020 Aug;30(8):639-648
pubmed: 32541866
Bioinformatics. 2011 Nov 1;27(21):2957-63
pubmed: 21903629
Int J Mol Sci. 2019 Apr 12;20(8):
pubmed: 31013709
Front Immunol. 2017 Mar 22;8:318
pubmed: 28382039
Mol Cell Biol. 2004 Feb;24(4):1640-8
pubmed: 14749379
Int J Cancer. 2008 Jul 1;123(1):8-13
pubmed: 18425818
Genes Dev. 2014 Mar 15;28(6):652-64
pubmed: 24637118
Genesis. 2004 May;39(1):52-7
pubmed: 15124227
Exp Dermatol. 2012 Dec;21(12):961-4
pubmed: 23171461
J Exp Med. 2020 Jul 6;217(7):
pubmed: 32315377
Immunity. 2011 May 27;34(5):637-50
pubmed: 21616434
J Immunol. 2015 Sep 1;195(5):1939-43
pubmed: 26223655
Nature. 2014 Jan 30;505(7485):691-5
pubmed: 24284630
Genes Dev. 2013 Sep 15;27(18):1959-73
pubmed: 24029918
Genome Biol. 2004;5(10):R80
pubmed: 15461798
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Cell. 2015 Aug 27;162(5):938-9
pubmed: 26317460
Curr Opin Genet Dev. 2019 Apr;55:46-51
pubmed: 31112907
J Invest Dermatol. 2014 Jul;134(7):1873-1883
pubmed: 24739813
Nat Cell Biol. 2017 Sep;19(9):1061-1070
pubmed: 28759028
Nature. 2020 Apr;580(7803):391-395
pubmed: 32296175
Nat Rev Genet. 2016 Sep 15;17(10):630-41
pubmed: 27629931
EMBO J. 2014 Mar 18;33(6):542-58
pubmed: 24514026
Mutat Res. 1993 Aug;300(3-4):165-77
pubmed: 7687016
Nat Methods. 2008 Jul;5(7):621-8
pubmed: 18516045
Immunity. 2006 May;24(5):633-42
pubmed: 16713980
Swiss Med Wkly. 2020 Aug 24;150:w20329
pubmed: 32920789
Cell. 2015 Aug 27;162(5):961-73
pubmed: 26317465
Nat Genet. 2001 Jan;27(1):31-9
pubmed: 11137995
Nucleic Acids Res. 2006 Jan 10;34(1):89-95
pubmed: 16407327
J Cell Biol. 2005 Aug 1;170(3):487-96
pubmed: 16061697
Cell Metab. 2019 Apr 2;29(4):871-885.e5
pubmed: 30853213
Mutagenesis. 2011 Jan;26(1):125-32
pubmed: 21164193
Nature. 2007 Feb 8;445(7128):648-51
pubmed: 17187052
Nature. 2020 Dec;588(7836):169-173
pubmed: 33087935
Biochem Biophys Res Commun. 2012 May 25;422(1):157-63
pubmed: 22564738
Nat Rev Genet. 2013 Mar;14(3):204-20
pubmed: 23400093
Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19386-91
pubmed: 23132945
Nucleic Acids Res. 2011 Jul;39(Web Server issue):W551-6
pubmed: 21565797
Mol Cell Biol. 2004 Aug;24(15):6719-27
pubmed: 15254239
Differentiation. 2005 Oct;73(8):406-13
pubmed: 16316411
J Neurosci. 2001 Feb 1;21(3):788-97
pubmed: 11157065
Annu Rev Immunol. 2019 Apr 26;37:247-267
pubmed: 30633609
Nature. 2018 Jul;559(7713):269-273
pubmed: 29973723
Immunity. 2001 Nov;15(5):763-74
pubmed: 11728338
Epigenetics Chromatin. 2014 Dec 02;7:35
pubmed: 25699092
Leukemia. 2018 May;32(5):1094-1105
pubmed: 29487386
Development. 2015 Jun 15;142(12):2163-72
pubmed: 26023099
Cell. 2015 Aug 27;162(5):974-86
pubmed: 26317466
Proc Natl Acad Sci U S A. 2003 Sep 30;100 Suppl 1:11830-5
pubmed: 12913119
Nature. 2017 Oct 19;550(7676):402-406
pubmed: 28976970
Nature. 2015 Jan 15;517(7534):321-6
pubmed: 25592537