The Death-inducer Obliterator 1 ( Dido1) Gene Regulates Embryonic Stem Cell Self- renewal*

Background:Dido1 plays important roles in development. Results:Dido1 inhibition led to ES cell differentiation, and its expression promoted ES cell self-renewal. Conclusion: Dido1 participates in ES cell maintenance and forms feedback and feedforward loops with canonical ES cell factors such as Nanog and Oct4. Significance: Dido1 represents a new factor in the ES cell regulatory circuitry for maintaining self-renewal of ES cells. 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