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bioRxiv · 10.1101/2025.09.23.677977

A STAT3-regulated lncRNA integrates microRNA biogenesis and sequestration to safeguard naive pluripotency

Giudice, V.·Perold, F.·Pijoff, Y.·Doerflinger, N.·Allegre, N.·Chazaud, C.·Aksoy, I.·Savatier, P.·Bourillot, P.-Y.
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Abstract

Leukemia inhibitory factor (LIF)/STAT3 signaling is central to maintaining naive pluripotency in mouse embryonic stem cells (mESCs). We identify Asgard, a previously uncharacterized long non-coding RNA, as a direct STAT3 target required for efficient self-renewal. Asgard is rapidly induced by LIF, enriched in the epiblast, and its depletion reduces alkaline phosphatase-positive colony formation while enhancing differentiation. Mechanistically, Asgard fulfils a dual role: it acts as the primary transcript for the differentiation-promoting microRNA Odin, while also functioning as a sponge to sequester Odin and related miRNAs. This dual mechanism enables Asgard to both generate and buffer pro-differentiation signals, thereby stabilizing the pluripotent state while preserving responsiveness to lineage cues. Our work reveals a new paradigm in RNA-mediated control of stem cell identity, where a single STAT3-regulated lncRNA couples microRNA production with competitive inhibition to safeguard naive pluripotency.

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Giudice, V., Perold, F., Pijoff, Y., Doerflinger, N., Allegre, N., Chazaud, C., Aksoy, I., Savatier, P., Bourillot, P.-Y.. 2025-09-25. A STAT3-regulated lncRNA integrates microRNA biogenesis and sequestration to safeguard naive pluripotency. https://doi.org/10.1101/2025.09.23.677977

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