Linc1557 is critical for the initiation of embryonic stem cell differentiation by directly targeting the LIF/STAT3 signaling pathway.

Embryonic stem cells (ESCs) have self-renewal and multi-lineage differentiation potential and perform critical functions in development and biomedicine. Several long noncoding RNAs (lncRNAs) have been reported as key regulators of stem cell pluripotency and differentiation. However, the function and regulatory mechanism of lncRNAs during the initiation of ESC differentiation remains unclear. Here, we found that linc1557 was highly expressed in mouse ESCs and required for the initiation of ESC differentiation. Knockdown of linc1557 increased the expression and phosphorylation levels of signal transducer and activator of transcription 3 (STAT3), a key factor in the leukemia inhibitory factor (LIF)/STAT3 signaling pathway. Furthermore, we found that linc1557 directly bound to Stat3 mRNA and affected its stability. The differentially expressed transcriptome after linc1557 knockdown in ESCs was involved primarily in multicellular organism development and cell differentiation as similar to that after Stat3 knockdown. Moreover, either knockdown of Stat3 or addition of a LIF/STAT3 signaling inhibitor rescued the suppressive effects of linc1557 knockdown on the initiation of mouse ESC differentiation. These findings not only elucidated the critical function of linc1557 in the initiation of mouse ESC differentiation but also clarified that its specific mechanism as directly affecting Stat3 mRNA stability, which enhanced the understanding of the lncRNA-mediated regulatory mechanism for mRNA stability and key signaling pathways in ESC pluripotency and differentiation.