Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation

A report of RNA 5-methylcytosine oxidation by mammalian Tet2, showing that Tet2 promotes infection-induced myelopoiesis in mice via a mechanism involving the repression of Socs3 mRNA, a previously unknown regulatory role of Tet2 at the epitranscriptomic level. mRNA oxidation mediates response to infection Messenger RNA (mRNA) can be modified biochemically without changing its ribonucleotide sequence. These mRNA modifications are essential for post-transcriptional regulation of gene expression. Xuetao Cao and colleagues report the oxidation of the RNA base 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC) by the mammalian Tet2 enzyme. The authors also show that Tet2 promotes infection-induced myelopoiesis—generation of innate immune cells from the bone marrow—in mice. This effect occurs through a mechanism involving the destabilization of Socs3 mRNA caused by decreased levels of 5-mC. These findings highlight the role of epitranscriptome modifications in mammalian physiology. 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 activity-independent way 6 . 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-w