Reactivation of the Paternal X Chromosome in Early Mouse Embryos

Abstract

It is generally accepted that paternally imprinted X inactivation occurs exclusively in extraembryonic lineages of mouse embryos, whereas cells of the embryo proper, derived from the inner cell mass (ICM), undergo only random X inactivation. Here we show that imprinted X inactivation, in fact, occurs in all cells of early embryos and that the paternal X is then selectively reactivated in cells allocated to the ICM. This contrasts with more differentiated cell types where X inactivation is highly stable and generally irreversible. Our observations illustrate that an important component of genome plasticity in early development is the capacity to reverse heritable gene silencing decisions.

Silence of the fathers: Early X inactivation

“…(3) The two studies concur that paternal X inactivation in preimplantation embryos is incomplete, with near complete silencing of genes closest to the XIC and partial or absent silencing of genes farther away from the XIC. (1,3) The unfinished nature of X p silencing in early development would presumably result in higher expression levels for some genes in females. This could explain the previously reported bimodal expression of some X-linked genes in mixtures of male and female preimplantation embryos.…”

“…Previous studies had suggested that genes may be expressed at a lower level from the X p in preimplantation embryos. (11)(12)(13) The current papers (1)(2)(3) that we discuss here further challenge the view that both X chromosomes are expressed in early stages of development by providing clear evidence of X p inactivation in preimplantation embryos.…”

“…Partial Xist RNA coating of the X p during early development (green-black gradient) correlates with incomplete silencing of genes on the X p . (1,3) Cot-1 has been found to be excluded from the Xist domain at the 2-cell stage (1) and RNA PolII excluded from the Xist domain at the 4-cell stage (2) (pink). Acetylated histone H3 (H3Ac) and methylated histone H3 lysine 4 (H3K4Me) become excluded along with Cot-1 and RNA PolII from the Xist domain at the 8-cell stage (2) (orange).…”

“…Accumulation of the Eed-Ezh2 protein complex (yellow circle), macroH2A variant (blue circle), and H3K27 di/tri-methylation (purple triangle) on the X p are first seen at the 16-cell morula stage. (2,3) Di-methylation of H3K9 (red triangle) on the X p is detected at the 32-cell blastocyst stage. Imprinted X p inactivation stabilizes as indicated by the more complete Xist coating (green) in extraembryonic tissues.…”

“…After the blastocyst implants, the inner cell mass (ICM) undergoes reactivation of the X p , as characterized by the loss of Xist coating, of Eed-Ezh2 and macroH2A accumulation, and of H3K27 and H3K9 methylation. (2,3) Cells of the embryo proper then undergo random inactivation in which either the X m or the X p are inactivated (green). Additional epigenetic changes, including hypoacetylation of histone H4, CpG island methylation and late replication (not depicted here), occur to insure stable X inactivation in somatic cells.…”