Abstract
The regulatory network of factors that center on master transcription factors such as Oct4, Nanog, and Sox2 help maintain embryonic stem (ES) cells and ensure their pluripotency. The target genes of these master transcription factors define the ES cell transcriptional landscape. In this study, we report our findings that Dido1, a target of canonical transcription factors such as Oct4, Sox2, and Nanog, plays an important role in regulating ES cell maintenance. We found that depletion of Dido1 in mouse ES cells led to differentiation, and ectopic expression of Dido1 inhibited differentiation induced by leukemia inhibitory factor withdrawal. We further demonstrated that whereas Nanog and Oct4 could occupy the Dido1 locus and promote its transcription, Dido1 could also target to the loci of pluripotency factors such as Nanog and Oct4 and positively regulate their expression. Through this feedback and feedforward loop, Dido1 is able to regulate self-renewal of mouse ES cells.
Highlights
We found the Dido1 isoform to have higher expression in mouse embryonic stem (ES) cells compared with mouse embryonic fibroblasts; the Dido3 isoform appeared to be expressed at a lower level in mouse ES cells compared with mouse embryonic fibroblasts (Fig. 1B), suggesting distinct roles for these two isoforms in mouse ES cells
When we examined Dido1 mRNA expression during differentiation, we found that the Dido1 level decreased Ͼ2-fold during differentiation induced by either Retinoic Acid (RA) treatment or leukemia inhibitory factor (LIF) withdrawal (Fig. 1C), suggesting that Dido1 may have an important function in mouse ES cells
To rule out the possibility that DIDO1-mediated inhibition of LIF withdrawal-induced differentiation and up-regulation of pluripotency factors was a result of activation of the LIF autocrine loop, we examined whether DIDO1 expression led to STAT3 phosphorylation and activation, because activation of STAT3 is a central pathway in LIF-dependent maintenance of mouse ES cells [28, 37, 38]
Summary
Conclusion: Dido participates in ES cell maintenance and forms feedback and feedforward loops with canonical ES cell factors such as Nanog and Oct. We report our findings that Dido, a target of canonical transcription factors such as Oct, Sox, and Nanog, plays an important role in regulating ES cell maintenance. We further demonstrated that whereas Nanog and Oct could occupy the Dido locus and promote its transcription, Dido could target to the loci of pluripotency factors such as Nanog and Oct and positively regulate their expression. Through this feedback and feedforward loop, Dido is able to regulate self-renewal of mouse ES cells. Dido Participates in ES Cell Maintenance light the importance of exploring the cross-talk between noncanonical pluripotency regulators and master transcription factors
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