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 XmXp^Δ 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.