RT Journal Article SR Electronic T1 Two coupled feedback loops explain random mono-allelic Xist upregulation at the onset of X-chromosome inactivation JF bioRxiv FD Cold Spring Harbor Laboratory SP 204909 DO 10.1101/204909 A1 Verena Mutzel A1 Ikuhiro Okamoto A1 Ilona Dunkel A1 Mitinori Saitou A1 Luca Giorgetti A1 Edith Heard A1 Edda G. Schulz YR 2017 UL http://biorxiv.org/content/early/2017/10/17/204909.abstract AB In female mammals, dosage compensation for X-linked genes is ensured through random X-chromosome inactivation, which is initiated by mono-allelic up-regulation of Xist. We use mathematical modeling to identify the regulatory principles required to establish the mono-allelic and female-specific Xist expression pattern and test model predictions experimentally. A cis-acting positive feedback, which in mice is mediated by mutual repression of Xist and its antisense transcript Tsix, together with a trans-acting negative feedback are sufficient to explain mono-allelic Xist up-regulation. The model can reproduce data from several mutant, aneuploid and polyploid murine cell lines and explains Xist expression patterns in other mammalian species. Furthermore, it predicts that transient, reversible bi-allelic Xist expression is not restricted to rabbits and humans but can also occur in mice, which we indeed confirm to occur in mouse embryos. Overall, our study provides a conceptual framework of the molecular mechanisms required to initiate random X-chromosome inactivation.