The mTORC1-TFE3-NuRD axis mediates pluripotent stem cells fate transition

Pluripotent stem cells (PSCs), which include embryonic stem cells (ESCs) derived from embryos and induced pluripotent stem cells (iPSCs) reprogrammed from somatic cells, possess significant application potential due to their ability to indefinitely self-renew while maintaining pluripotency. However, many aspects of PSC fate transitions remain poorly understood. Hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) by deficiency of its upstream repressors TSC1/2 is known to impede both pluripotency re-establishment and exit. Yet, the detailed mechanism by which mTORC1 regulates transcription critical for these transitions, and whether similar mechanisms underlie both processes, remains unclear. In this study, we demonstrate that mTORC1 induces the nuclear translocation of transcription factor TFE3, which binds to the nucleosome remodeling and deacetylation complex NuRD. This interaction leads to the repression of specific target genes crucial for pluripotency re-establishment and exit. Our findings highlight that the mTORC1-TFE3-NuRD axis acts as a transcriptional repressor in PSC fate transitions through regulation of chromatin remodeling modifications. These findings contribute to a better understanding of how mTORC1 governs the intricate regulation of PSC fate transitions, which is relevant to diverse fields including development, metabolic diseases, cancer, and aging.