Person:

Triboulet, Robinson

The pluripotency factor Lin28 blocks the expression of let-7 microRNAs (miRNAs) in undifferentiated cells during development and functions as an oncogene in a subset of cancers1. Lin28 binds to let-7 precursor RNAs and recruits 3′ terminal uridylyl transferases (TUTases) to selectively inhibit let-7 biogenesis2–4. Uridylated pre-let-7 is refractory to processing by Dicer and is rapidly degraded by an unknown ribonuclease5. Here we identify Dis3l2 as the 3′-5′ exonuclease responsible for the decay of uridylated pre-let-7. Biochemical reconstitution assays reveal that 3′ oligouridylation stimulates Dis3l2 activity in vitro, and knockdown of Dis3l2 in mouse embryonic stem cells leads to the stabilization of pre-let-7. Our study establishes 3′ oligouridylation as an RNA decay signal for Dis3l2 and identifies the first physiological RNA substrate of this novel exonuclease that is mutated in the Perlman syndrome of fetal overgrowth and predisposition to Wilms’ tumor6.

Signaling and post-transcriptional gene control are both critical for the regulation of pluripotency1,2, yet how they are integrated to influence cell identity remains poorly understood. LIN28 (also known as LIN28A), a highly conserved RNA-binding protein (RBP), has emerged as a central post-transcriptional regulator of cell fate through blockade of let-7 microRNA (miRNA) biogenesis and direct modulation of mRNA translation3. Here we show that LIN28 is phosphorylated by MAPK/ERK in pluripotent stem cells (PSCs), which increases its levels via post-translational stabilization. LIN28 phosphorylation had little impact on let-7 but enhanced LIN28’s effect on its direct mRNA targets, revealing a mechanism that uncouples LIN28’s let-7-dependent and independent activities. We have linked this mechanism to the induction of pluripotency by somatic cell reprogramming and the transition from naïve to primed pluripotency. Collectively, our findings indicate that MAPK/ERK directly impacts LIN28, defining an axis that connects signaling, post-transcriptional gene control, and cell fate regulation.