DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages

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DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages
 
Cobo, Isidoro; Tanaka, Tiffany N; Chandra Mangalhara, Kailash; Lana, Addison; Yeang, Calvin; Han, Claudia; Schlachetzki, Johannes; Challcombe, Jean; Fixsen, Bethany R; Sakai, Mashito; Li, Rick Z; Fields, Hannah; Mokry, Michal; Tsai, Randy G; Bejar, Rafael; Prange, Koen; de Winther, Menno; Shadel, Gerald S; Glass, Christopher K
(2022) Immunity, volume 55, issue 8, pp. 1386 - 1401.e10
(Article)
Abstract
Deleterious somatic mutations in DNA methyltransferase 3 alpha (DNMT3A) and TET mehtylcytosine dioxygenase 2 (TET2) are associated with clonal expansion of hematopoietic cells and higher risk of cardiovascular disease (CVD). Here, we investigated roles of DNMT3A and TET2 in normal human monocyte-derived macrophages (MDM), in MDM isolated from individuals with ... read more
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Keywords: Cardiovascular Diseases, DNA Methyltransferase 3A, DNA, Mitochondrial/genetics, DNA-Binding Proteins/genetics, Dioxygenases/genetics, Humans, Interferons/metabolism, Macrophages/metabolism, Mitochondria/genetics, Mutation/genetics, Nucleotidyltransferases/metabolism, Proto-Oncogene Proteins/genetics, Trans-Activators/metabolism, atherosclerosis, clonal hematopoiesis, transcriptional regulation, DNMT3A, TET2, mitochondria DNA, interferon, TFAM, Infectious Diseases, Immunology and Allergy, Immunology, Journal Article
DOI: https://doi.org/10.1016/j.immuni.2022.06.022
ISSN: 1074-7613
Publisher: Cell Press
Note: Funding Information: This work was supported by a Leducq Transatlantic Network Grant 16CVD01 (C.K.G., M.d.W.), NIH P01 HL147835 (C.K.G.), EMBO ALTF 960-2018 (IC), R0 AR069876 , and the Audrey Geisel Chair in Biomedical Sciences (G.S.S.), Salkexcellerators Postdoctoral Fellowship (K.C.M.), ZonMW 09120011910025 (M.d.W.), the National Headache Foundation (GENIUSII and 2019B016 to M.d.W.), NS047101 (Confocal Microscopy Core), 1KL2TR001444 (T.N.T.).We acknowledge P.M., B.F., C.N., M.H., S.D., Y.A., G.S., J.S., T.P., H.B., J.S., donors from the San Diego Blood Bank, and from the Normal Blood Program of Scripps for having provided blood. We also acknowledge Jana Collier and Martina Pasillas for technical assistance; Ali Shilatifard for providing the TET2 antibody used for ChIP-seq; the electron microscopy core at the School of Medicine at the Univeristy of California, San Diego; the Microscopy Unit Core at the School of Medicine; Laura Antonucci, Elsa Lopez (Michael Karin’s Laboratory, UCSD) for help in doing confocal imaging of MDM; and to LVA for essential drafting of figures. Funding Information: This work was supported by a Leducq Transatlantic Network Grant 16CVD01(C.K.G. M.d.W.), NIH P01 HL147835 (C.K.G.), EMBO ALTF 960-2018 (IC), R0 AR069876, and the Audrey Geisel Chair in Biomedical Sciences (G.S.S.), Salkexcellerators Postdoctoral Fellowship (K.C.M.), ZonMW 09120011910025 (M.d.W.), the National Headache Foundation (GENIUSII and 2019B016 to M.d.W.), NS047101 (Confocal Microscopy Core), 1KL2TR001444 (T.N.T.).We acknowledge P.M. B.F. C.N. M.H. S.D. Y.A. G.S. J.S. T.P. H.B. J.S. donors from the San Diego Blood Bank, and from the Normal Blood Program of Scripps for having provided blood. We also acknowledge Jana Collier and Martina Pasillas for technical assistance; Ali Shilatifard for providing the TET2 antibody used for ChIP-seq; the electron microscopy core at the School of Medicine at the Univeristy of California, San Diego; the Microscopy Unit Core at the School of Medicine; Laura Antonucci, Elsa Lopez (Michael Karin's Laboratory, UCSD) for help in doing confocal imaging of MDM; and to LVA for essential drafting of figures. Conceptualization: I.C. K.C.M. G.S.S. C.K.G.; data curation: I.C. J.C. K.P. M.M.; formal analyses: I.C. J.C. K.P.; funding acquisition: I.C. T.N.T. C.Y. R.B. C.K.G.; investigation: I.C. A.L. C.H. B.R.F. J.S. T.N.T. C.Y.; methodology: I.C. A.L. C.H. J.S. T.N.T. R.G.T. M.M.; supervision: C.K.G.; visualization: I.C. C.K.G.; writing: I.C. K.C.M. G.S.S. C.K.G.; review & editing: I.C. K.C.M. G.S.S. T.N.T. C.Y. J.S. R.B. B.R.F. M.d.W. K.P. C.H. C.K.G. C.K.G. is a cofounder and member of the scientific advisory board of Asteroid Therapeutics. Publisher Copyright: © 2022 Elsevier Inc.
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