In mice, imprinted inactivation of the paternal X chromosome occurs in the pre-implantation female embryo and is maintained in the extraembryonic tissue. Paternal X chromosome inactivation is triggered by the monoallelic, paternal expression of the Xist non-coding RNA. In normal circumstances, imprinted XCI achieves gene balance: both male and female embryos have one and only one active X per cell.
Smchd1 is a known factor mediating gene silencing on the inactive X and a certain autosomal genes. Using single-E2.75-embryo methylome and transcriptome sequencing as well as allele-specific RNA FISH, we show that the oocyte supply of Smchd1 is required to repress Xist expression on the maternal allele. In the absence of maternal Smchd1, both X chromosomes in females and the only X in males undergo silencing. Furthermore, loss of maternal Smchd1 has surprisingly long lasting effects: at E14.5, despite the presence of zygotic Smchd1 for over 11 days, CpG islands on the paternal X remain hypomethylated and gene expression is upregulated compared to wild-type.
These data reveal a new role for Smchd1 in the initiation of imprinted X inactivation, via the allele-specific silencing of Xist.