Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 294, Issue 47, Pages 17863-17874Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.010284
Keywords
microRNA (miRNA); long noncoding RNA (long ncRNA; lncRNA); reprogramming; gene regulation; induced pluripotent stem cell (iPS cell) (iPSC); cellular reprogramming; circular RNA (circRNA); competing endogenous RNA (ceRNA); long intergenic noncoding RNA (lincRNA); microRNA (miRNA)
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Funding
- Natural Science Foundation of Heilongjiang Province Grant [C2018032]
- National Key Research and Development program of China-Stem Cell and Translational Research Grant [2016-YFA0100200]
- Starr Foundation Tri-Institutional Stem Cell Core and Derivation grant
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Long noncoding RNAs (lncRNAs) modulate gene expression as competing endogenous RNAs (ceRNAs) that sponge regulatory microRNAs (miRNAs). During cellular reprogramming, genes associated with pluripotency establishment need to be up-regulated, and developmental genes need to be silenced. However, how ceRNAs control cellular reprogramming still awaits full elucidation. Here, we used doxycycline-inducible expression of the four transcription factors octamer-binding protein 4 (OCT4), SRY-box 2 (SOX2), Kr?ppel-like factor 4 (KLF4), and proto-oncogene c-Myc (c-Myc) to generate induced pluripotent stem cells (iPSCs) from mouse embryonic fibroblasts (MEFs). Using RNA-Seq and bioinformatics approaches, we found that the expression levels of miRNAs from MEFs remain high from day 0 to 6 after the doxycycline induction. Many genes targeted by these miRNAs were up-regulated, and long intergenic noncoding RNAs (lincRNAs) and circular RNAs (circRNAs), which have complementary binding sites to these miRNAs, were highly expressed, indicating lincRNAs and circRNAs may function as ceRNAs. Intriguingly, knockdown of the linc/circRNAs that sponge the miRNAs, which target OCT4 down-regulated exogenous OCT4, decreased reprogramming efficiency, and resulted in low-grade iPSCs. Our results suggest that the ceRNA network plays an important role in cellular reprogramming.
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