Epigenetic Dynamics of Imprinted X Inactivation During Early Mouse Development

Abstract

The initiation of X-chromosome inactivation is thought to be tightly correlated with early differentiation events during mouse development. Here, we show that although initially active, the paternal X chromosome undergoes imprinted inactivation from the cleavage stages, well before cellular differentiation. A reversal of the inactive state, with a loss of epigenetic marks such as histone modifications and polycomb proteins, subsequently occurs in cells of the inner cell mass (ICM), which give rise to the embryo-proper in which random X inactivation is known to occur. This reveals the remarkable plasticity of the X-inactivation process during preimplantation development and underlines the importance of the ICM in global reprogramming of epigenetic marks in the early embryo.

Silence of the fathers: Early X inactivation

“…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).…”

“…(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.…”

“…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.…”