Tet2 promotes pathogen infection-induced myelopoiesis through mRNA oxidation

Abstract

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.

Environmental influences on clonal hematopoiesis

“…TET2 is an epigenetic modifier that is frequently mutated across myeloid malignancies. In CH, TET2 is the second most frequently mutated gene, and growing evidence suggests that factors including secondary genetic alterations [43,44], inflammation [40,45,46], and changes in the microbiota [10] may contribute to the clonal expansion and preleukemic condition of TET2-mutant hematopoietic stem and progenitor cells (HSPCs). Here, we discuss the biological studies investigating environmental influences on HSPCs with TET2 loss of function (LOF) in CH.…”

Discovering and Mapping the Modified Nucleotides That Comprise the Epitranscriptome of mRNA

“…5-hydoxymethyl cytosine is an oxidized product of m 5 C and was originally mapped in Drosophila mRNA (Delatte et al 2016). 5hydoxymethyl cytosine has recently been proposed to be present also in mammalian mRNA (Shen et al 2018). 8oxo-G has also been detected in mRNA, and is largely thought to represent a product of oxidative damage (Shan et al 2003).…”

“…A recent study investigating the function of the Tet2 dioxygenase in mice used bisulfite sequencing to identify m 5 C sites that were not converted to 5hmC in Tet2 knockout animals (Shen et al 2018). This revealed that m 5 C and hm 5 C might be used to control mRNA secondary structure and thereby regulate recognition by RNA binding proteins during the immune response (Shen et al 2018).…”

Identification and quantification of modified nucleosides inSaccharomyces cerevisiaemRNAs

“…Our systematic data analyses and exclusive assignment of highly retained, abundant modifications to mRNAs are particularly important in light of the current dialogue regarding prevalence of several mRNA modifications. While the groundbreaking studies that mapped m 5 C and m 1 A to the transcriptome seemed to indicate that these modifications are incorporated at thousands of sites, follow-up reports reach contradictory conclusions -some suggest that these modifications may only be present in a handful of mRNAs, while others support the initial finding that they are common (Edelheit et al 2013;Li et al 2016;Legrand et al 2017;Safra et al 2017;Guallar et al 2018;Shen et al 2018).…”