LincU Preserves Naive Pluripotency by Restricting ERK Activity in Embryonic Stem Cells [overexpression]

While the functional roles of long non-coding RNAs (lncRNAs) have been increasingly identified, few lncRNAs that control the naive state of embryonic stem cells (ESCs) are known. Here, we report a naive-state-associated lncRNA, lincU, which is intrinsically activated by NANOG in naive mESCs. LincU-deficient mESCs exhibit a primed-like pluripotent state and potentiate the transition from naive state to primed state, whereas ectopic lincU expression maintains mESCs in the naive state. Mechanistically, we demonstrate that lincU directly binds and stabilizes the DUSP9 protein, an ERK-specific phosphatase, and then constitutively inhibits the ERK1/2 signaling pathway, which critically contributes to maintenance of the naive state. Importantly, we reveal the functional role of lincU to be evolutionarily conserved in human. Our findings thus unveil lincU as a conserved lncRNA that intrinsically restricts MAPK/ERK activity and maintains the naive state of ESCs.

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