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

Isidoro Cobo, Tiffany N. Tanaka, Kailash Chandra Mangalhara, Addison Lana, Calvin Yeang, Claudia Han, Johannes Schlachetzki, Jean Challcombe, Bethany R. Fixsen, Mashito Sakai, Rick Z. Li, Hannah Fields, Michal Mokry, Randy G. Tsai, Rafael Bejar, Koen Prange, Menno de Winther, Gerald S. Shadel, Christopher K. Glass

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)


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 languageEnglish
Pages (from-to)1386-1401.e10
Number of pages16
Issue number8
Early online date4 Aug 2022
Publication statusPublished - 9 Aug 2022


  • DNMT3A
  • TET2
  • TFAM
  • atherosclerosis
  • clonal hematopoiesis
  • interferon
  • mitochondria DNA
  • transcriptional regulation

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