Regulatory principles and mechanisms governing the onset of random X-chromosome inactivation

X-chromosome inactivation (XCI) has evolved in mammals to compensate for the difference in X-chromosomal dosage between the sexes. In placental mammals, XCI is initiated during early embryonic development through upregulation of the long noncoding RNA Xist from one randomly chosen X chromosome in each female cell. The Xist locus must thus integrate both X-linked and developmental trans-regulatory factors in a dosage-dependent manner. Furthermore, the two alleles must coordinate to ensure inactivation of exactly one X chromosome per cell. In this review, we summarize the regulatory principles that govern the onset of XCI. We go on to provide an overview over the factors that have been implicated in Xist regulation and discuss recent advances in our understanding of how Xist’s cis-regulatory landscape integrates information in a precise fashion.