X chromosome inactivation (XCI) in female placental mammals is a vital mechanism for dosage compensation between X-linked and autosomal genes. XCI starts with activation of Xist and silencing of the negative regulator Tsix, followed by cis spreading of Xist RNA over the future inactive X chromosome (Xi). Here, we show that XCI does not require physical contact between the two X chromosomes (X-pairing) but is regulated by trans-acting diffusible factors. We found that the X-encoded trans-acting and dose-dependent XCI-activator RNF12 acts in concert with the cis-regulatory region containing Jpx, Ftx, and Xpr to activate Xist and to overcome repression by Tsix. RNF12 acts at two subsequent steps; two active copies of Rnf12 drive initiation of XCI, and one copy needs to remain active to maintain XCI toward establishment of the Xi. This two-step mechanism ensures that XCI is very robust and fine-tuned, preventing XCI of both X chromosomes. © 2014 Elsevier Inc.
Barakat, T. S., Loos, F., Van Staveren, S., Myronova, E., Ghazvini, M., Grootegoed, J. A., & Gribnau, J. (2014). The trans-activator RNF12 and cis-acting elements effectuate X chromosome inactivation independent of X-pairing. Molecular Cell, 53(6), 965–978. https://doi.org/10.1016/j.molcel.2014.02.006