Proposed model.

(a) Irreversible Xm-Xist imprinting. The transient alteration of histone modifications through loss of H3K9me3 and gain of histone acetylation induces stable Xm-Xist derepression and results in the rescue of lethality in XmXpΔ without gene manipulation. The imprinting switch in XCI does not affect cellular integrity. (b) Maintenance and erasure of the Xm-Xist imprint. In early preimplantation phases, chromatin at Xm-Xist/Tsix regions is condensed by various epigenetic modifications. At late stage, Oct4 localizes to nucleus (see discussion) and serves as a chromatin opener at Xm-Xist/Tsix regions, creating transcriptional permissive states around Xist/Tsix regions. In XmXm embryos, Rnf12 expression levels represent a double dose compared with those of XmY or XmXp embryos, leading to Xm-Xist activation by Tsix silencing, which depends on REX1 state. In XmY and XmXp embryos, on the other hand, physiological expression levels of Rnf12 are essential for Xm-Xist silencing by Xm-Tsix activation.