A symmetric toggle switch explains the onset of random X inactivation in different mammals

Summary Gene-regulatory networks control establishment and maintenance of alternative gene expression states during development. A particular challenge is the acquisition of opposing states by two copies of the same gene, as it is the case in mammals for Xist at the onset of random X-chromosome inactivation (XCI). The regulatory principles that lead to stable mono-allelic expression of Xist remain unknown. Here, we uncovered the minimal Xist regulatory network, by combining mathematical modeling and experimental validation of central model predictions. We identified a symmetric toggle switch as the basis for random mono-allelic Xist up-regulation, which reproduces data from several mutant, aneuploid and polyploid murine cell lines with various Xist expression patterns. Moreover, this toggle switch explains the diversity of strategies employed by different species at the onset of XCI. In addition to providing a unifying conceptual framework to explore X-chromosome inactivation across mammals, our study sets the stage for identifying the molecular mechanisms required to initiate random XCI.