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 DNMT3A or TET2 mutations, and in macrophages isolated from human atherosclerotic plaques. We found that loss of function of DNMT3A or TET2 resulted in a type I interferon response due to impaired mitochondrial DNA integrity and activation of cGAS signaling. DNMT3A and TET2 normally maintained mitochondrial DNA integrity by regulating the expression of transcription factor A mitochondria (TFAM) dependent on their interactions with RBPJ and ZNF143 at regulatory regions of the TFAM gene. These findings suggest that targeting the cGAS-type I IFN pathway may have therapeutic value in reducing risk of CVD in patients with DNMT3A or TET2 mutations.
| Original language | English |
|---|---|
| Pages (from-to) | 1386-1401.e10 |
| Number of pages | 16 |
| Journal | Immunity |
| Volume | 55 |
| Issue number | 8 |
| Early online date | 4 Aug 2022 |
| DOIs | |
| Publication status | Published - 9 Aug 2022 |
Keywords
- DNMT3A
- TET2
- TFAM
- atherosclerosis
- clonal hematopoiesis
- interferon
- mitochondria DNA
- transcriptional regulation
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In: Immunity, Vol. 55, No. 8, 09.08.2022, p. 1386-1401.e10.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages
AU - Cobo, Isidoro
AU - Tanaka, Tiffany N.
AU - Chandra Mangalhara, Kailash
AU - Lana, Addison
AU - Yeang, Calvin
AU - Han, Claudia
AU - Schlachetzki, Johannes
AU - Challcombe, Jean
AU - Fixsen, Bethany R.
AU - Sakai, Mashito
AU - Li, Rick Z.
AU - Fields, Hannah
AU - Mokry, Michal
AU - Tsai, Randy G.
AU - Bejar, Rafael
AU - Prange, Koen
AU - de Winther, Menno
AU - Shadel, Gerald S.
AU - Glass, Christopher K.
N1 - 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.
PY - 2022/8/9
Y1 - 2022/8/9
N2 - 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 DNMT3A or TET2 mutations, and in macrophages isolated from human atherosclerotic plaques. We found that loss of function of DNMT3A or TET2 resulted in a type I interferon response due to impaired mitochondrial DNA integrity and activation of cGAS signaling. DNMT3A and TET2 normally maintained mitochondrial DNA integrity by regulating the expression of transcription factor A mitochondria (TFAM) dependent on their interactions with RBPJ and ZNF143 at regulatory regions of the TFAM gene. These findings suggest that targeting the cGAS-type I IFN pathway may have therapeutic value in reducing risk of CVD in patients with DNMT3A or TET2 mutations.
AB - 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 DNMT3A or TET2 mutations, and in macrophages isolated from human atherosclerotic plaques. We found that loss of function of DNMT3A or TET2 resulted in a type I interferon response due to impaired mitochondrial DNA integrity and activation of cGAS signaling. DNMT3A and TET2 normally maintained mitochondrial DNA integrity by regulating the expression of transcription factor A mitochondria (TFAM) dependent on their interactions with RBPJ and ZNF143 at regulatory regions of the TFAM gene. These findings suggest that targeting the cGAS-type I IFN pathway may have therapeutic value in reducing risk of CVD in patients with DNMT3A or TET2 mutations.
KW - DNMT3A
KW - TET2
KW - TFAM
KW - atherosclerosis
KW - clonal hematopoiesis
KW - interferon
KW - mitochondria DNA
KW - transcriptional regulation
UR - http://www.scopus.com/inward/record.url?scp=85135508102&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.immuni.2022.06.022
DO - https://doi.org/10.1016/j.immuni.2022.06.022
M3 - Article
C2 - 35931086
SN - 1074-7613
VL - 55
SP - 1386-1401.e10
JO - Immunity
JF - Immunity
IS - 8
ER -