Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation

Nature. 2018 Feb 1;554(7690):123-127. doi: 10.1038/nature25434. Epub 2018 Jan 24.


Varieties of RNA modification form the epitranscriptome for post-transcriptional regulation. 5-Methylcytosine (5-mC) is a sparse RNA modification in messenger RNA (mRNA) under physiological conditions. The function of RNA 5-hydroxymethylcytosine (5-hmC) oxidized by ten-eleven translocation (Tet) proteins in Drosophila has been revealed more recently. However, the turnover and function of 5-mC in mammalian mRNA have been largely unknown. Tet2 suppresses myeloid malignancies mostly in an enzymatic activity-dependent manner, and is important in resolving inflammatory response in an enzymatic activity-independent way. Myelopoiesis is a common host immune response in acute and chronic infections; however, its epigenetic mechanism needs to be identified. Here we demonstrate that Tet2 promotes infection-induced myelopoiesis in an mRNA oxidation-dependent manner through Adar1-mediated repression of Socs3 expression at the post-transcription level. Tet2 promotes both abdominal sepsis-induced emergency myelopoiesis and parasite-induced mast cell expansion through decreasing mRNA levels of Socs3, a key negative regulator of the JAK-STAT pathway that is critical for cytokine-induced myelopoiesis. Tet2 represses Socs3 expression through Adar1, which binds and destabilizes Socs3 mRNA in a RNA editing-independent manner. For the underlying mechanism of Tet2 regulation at the mRNA level, Tet2 mediates oxidation of 5-mC in mRNA. Tet2 deficiency leads to the transcriptome-wide appearance of methylated cytosines, including ones in the 3' untranslated region of Socs3, which influences double-stranded RNA formation for Adar1 binding, probably through cytosine methylation-specific readers, such as RNA helicases. Our study reveals a previously unknown regulatory role of Tet2 at the epitranscriptomic level, promoting myelopoiesis during infection in the mammalian system by decreasing 5-mCs in mRNAs. Moreover, the inhibitory function of cytosine methylation on double-stranded RNA formation and Adar1 binding in mRNA reveals its new physiological role in the mammalian system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • 5-Methylcytosine / analogs & derivatives
  • 5-Methylcytosine / metabolism
  • Adenosine Deaminase / metabolism
  • Animals
  • Bone Marrow Cells / immunology
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation
  • Immunity, Innate
  • Mice
  • Myelopoiesis* / genetics
  • Nucleic Acid Conformation
  • Oxidation-Reduction
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / metabolism*
  • RNA, Double-Stranded / chemistry
  • RNA, Double-Stranded / genetics
  • RNA, Double-Stranded / metabolism
  • RNA, Messenger / chemistry*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Sepsis / genetics*
  • Sepsis / microbiology*
  • Suppressor of Cytokine Signaling 3 Protein / genetics
  • Transcriptome / genetics


  • 3' Untranslated Regions
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • RNA, Double-Stranded
  • RNA, Messenger
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Dioxygenases
  • Tet2 protein, mouse
  • ADAR1 protein, mouse
  • Adenosine Deaminase