Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation

Varieties of RNA modification form the epitranscriptome for post-transcriptional regulation(1). 5-Methylcytosine (5-mC) is a sparse RNA modification in messenger RNA (mRNA) under physiological conditions(2). The function of RNA 5-hydroxymethylcytosine (5-hmC) oxidized by ten-eleven translocation (Tet) proteins in Drosophila has been revealed more recently(3,4). 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(5), and is important in resolving inflammatory response in an enzymatic activityindependent way6. 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 Adar(1)-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 Socs(3), 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. Tet(2) deficiency leads to the transcriptome-wide appearance of methylated cytosines, including ones in the 3 ' untranslated region of Socs(3), which influences double-stranded RNA formation for Adar(1) 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.