N6-methyladenosine (m6A) is the most common and abundant messenger RNA modification, modulated by ‘writers’, ‘erasers’ and ‘readers’ of this mark1,2. In vitro data have shown that m6A influences all fundamental aspects of mRNA metabolism, mainly mRNA stability, to determine stem cell fates3,4. However, its in vivo physiological function in mammals and adult mammalian cells is still unknown. Here we show that the deletion of m6A ‘writer’ protein METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopaenic mouse adoptive transfer model, naive Mettl3-deficient T cells failed to undergo homeostatic expansion and remained in the naive state for up to 12 weeks, thereby preventing colitis. Consistent with these observations, the mRNAs of SOCS family genes encoding the STAT signalling inhibitory proteins SOCS1, SOCS3 and CISH were marked by m6A, exhibited slower mRNA decay and showed increased mRNAs and levels of protein expression in Mettl3-deficient naive T cells. This increased SOCS family activity consequently inhibited IL-7-mediated STAT5 activation and T cell homeostatic proliferation and differentiation. We also found that m6A has important roles for inducible degradation of Socs mRNAs in response to IL-7 signalling in order to reprogram naive T cells for proliferation and differentiation. Our study elucidates for the first time, to our knowledge, the in vivo biological role of m6A modification in T-cell-mediated pathogenesis and reveals a novel mechanism of T cell homeostasis and signal-dependent induction of mRNA degradation.
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Gene Expression Omnibus
We thank R. Flynn, R. Jackson, Y. Yang, M. Vesely, R. Paiva, N. Palm and all the other members of the Flavell laboratory for discussions and comments. We thank J. Alderman, C. Lieber, C. Hughes and J. Stein for technical support. H.-B.L. was supported by NIH T32 2T32DK007356. S.Z was supported by a fellowship from Helen Hay Whitney Foundation-Howard Hughes Medical Institute. This work was supported by the Howard Hughes Medical Institute (R.A.F.), NSF Major International Joint Research Program of China - 31420103901 (Z.Y. and R.A.F.) and ‘111’ project (Z.Y.), R01-HG004361 (H.Y.C.), NIH New Innovator Award DP2 HD083992-01 (M.D.S.), and a Searle scholarship (M.D.S.).
Extended data figures
This table contains a list of all the antibodies and reagents used in this study.
This table contains a list of all the primers used in this study.
This table contains two lists of up-regulated and down-regulated genes by RNA-Seq of Mettl3 KO and WT Naïve T cells.
This table contains a list of top 20 up-regulated and down-regulated Ribosome occupancy of Mettl3 KO and WT mRNAs by Ribosome profiling in this study.
This table contains lists of all the clusters revealed by s4U-Seq of Mettl3 KO and WT naïve T cells in response to IL-7 stimulation over times in this study. Each tab contains one cluster determined by similar time-dependent expression profile changes after IL-7 induction.
About this article
Molecular Cancer (2019)