mTORC1 hyperactivation blocks pluripotent stem cells fate transitions through TFE3-NuRD association [RNA-Seq]

As an evolutionarily conserved master regulator of metabolism, mechanistic target of rapamycin complex 1 (mTORC1) regulates cell states and fates in development, cancer and aging. mTORC1 activity regulation was critical for pluripotent stem cells maintenance and cell fate transitions. Inhibition of mTORC1 induces embryonic stem cells (ESCs) entry into a paused state which reversibly arrests self-renewal leaving pluripotency intact. Hyperactivation of mTORC1 impedes both pluripotency re-establishment and exit of PSCs. As shown that mTORC1 mediates TFE3 nuclear translocation block pluripotency exit, whether similar mechanisms through transcription factor TFE3 are involved in these processes, and the detailed mechanism by which mTORC1-TFE3 regulates critical transcriptional processes for these transitions, remain unclear. In this study, we demonstrate that the nuclear translocation of TFE3, induced by hyperactivation of mTORC1, results in its binding to the nucleosome remodeling and deacetylation (NuRD) complex in both re-establishment and exit of pluripotency. This interaction inhibits the expression of various crucial genes during different fate transitions of PSCs. Our findings uncover a common and key role of TFE3-NuRD association as mediator of mTORC1 to block pluripotent cell fate transitions, with implications for various fields including physiological and pathological diseases. RNA-seq data included Tsc1 loxp/loxp MEFs cells with or without AAV-cre cleavage (Tsc1 WT and Tsc1 KO), and reprogrammed cells with ectopically expressed OSKM (Oct4, Sox2, Klf4, c-Myc),along with either control transfection(shLuc) or two shRNAs for Tfe3 Knockdown. Two time points in the reprogramming time course were profiled: Day 5(early) and Day 10 (late)