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Deciphering the Role of Long Non-coding RNAs in ESC Differentiation

Review of “Linc1557 is critical for the initiation of embryonic stem cell differentiation by directly targeting the LIF/STAT3 signaling pathway” from STEM CELLS by Stuart P. Atkinson

Previous research has highlighted critical roles for long non-coding RNAs (lncRNAs) in the regulation of stem cell characteristics [1, 2]; however, the exact function and regulatory mechanism of lncRNAs during the initiation of embryonic stem cell (ESC) differentiation currently remains unclear. 

Reporting in a new STEM CELLS study [3], researchers led by Guiying Wang and Jiuhong Kang (Tongji University, Shanghai, China) report that linc1557, previously identified in a screen aiming to identify large intergenic non-coding RNAs (lincRNAs) critical to pluripotency and differentiation [4], inhibits mouse ESC differentiation by regulating signaling via the leukemia inhibitory factor (LIF)/signal transducer and activator of transcription 3 (STAT3) pathway [5-8].

After confirming the elevated levels of linc1557 in ESCs and establishing its cytoplasmic localization and rapid silencing during differentiation, Lan et al. employed bioinformatic prediction and experimental verification to determine that linc1557 directly binds to Stat3 mRNA to decrease its stability. Accordingly, the knockdown of linc1557 by RNA interference prompted an increase in the expression of STAT3 mRNA and protein and enhanced STAT3 phosphorylation, suggesting the activation of the LIF/STAT3 signaling pathway; furthermore, linc1557 knockdown ESCs maintained their pluripotent nature and the authors found evidence for a block in early mESC differentiation. Transcriptional analysis following linc1557 knockdown demonstrated a similar response to Stat3 knockdown – the deregulation of genes primarily involved in multicellular organism development and cell differentiation in mESCs.

Overall, the authors provide evidence for a critical role for linc1557 in the initiation of mouse ESC differentiation and further widen our appreciation of the epigenetic signaling network controlling the normal differentiation of ESCs.

For more on how lncRNAs regulate the pluripotency and differentiation of ESCs, stay tuned to the Stem Cells Portal!

References

  1. Lin N, Chang K-Y, Li Z, et al., An Evolutionarily Conserved Long Noncoding RNA TUNA Controls Pluripotency and Neural Lineage Commitment. Molecular Cell 2014;53:1005-1019.
  2. Wang Y, He L, Du Y, et al., The Long Noncoding RNA lncTCF7 Promotes Self-Renewal of Human Liver Cancer Stem Cells through Activation of Wnt Signaling. Cell Stem Cell 2015;16:413-425.
  3. Lan Y, Lu C, Yang Y, et al., Linc1557 is critical for the initiation of embryonic stem cell differentiation by directly targeting the LIF/STAT3 signaling pathway. STEM CELLS 2020;38:340-351.
  4. Guttman M, Donaghey J, Carey BW, et al., lincRNAs act in the circuitry controlling pluripotency and differentiation. Nature 2011;477:295-300.
  5. Niwa H, Burdon T, Chambers I, et al., Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes & Development 1998;12:2048-2060.
  6. Zhou X, Smith AJH, Waterhouse A, et al., Hes1 Desynchronizes Differentiation of Pluripotent Cells by Modulating STAT3 Activity. STEM CELLS 2013;31:1511-1522.
  7. Yang J, van Oosten AL, Theunissen TW, et al., Stat3 Activation Is Limiting for Reprogramming to Ground State Pluripotency. Cell Stem Cell 2010;7:319-328.
  8. Bourillot P-Y, Aksoy I, Schreiber V, et al., Novel STAT3 Target Genes Exert Distinct Roles in the Inhibition of Mesoderm and Endoderm Differentiation in Cooperation with Nanog. STEM CELLS 2009;27:1760-1771.