Model for X inactivation in the female mouse embryo. (a) Sperm bearing an X chromosome (the paternal X or Xp) have epigenetic marks (blue flags), leading to transcriptional repression of a portion of the chromosome. (b) In the female embryo (XX) these marks carry over through fertilization and the first cleavages. (c) From the two-cell to the eight-cell stage, a separate mechanism establishes additional marks (red flags) on the paternal X, repressing transcription at most loci. The maternal X chromosome (Xm) is unaffected. (d) In the blastocyst, repression of the paternal X is maintained in trophectoderm cells that will go on to form the trophoblast (an extraembryonic lineage) but is lifted in cells of the inner cell mass (ICM) (which are fated to form the embryo proper), where X inactivation now occurs randomly (green flags). (e) This state is maintained through later development, in which the paternal X is inactive in extraembryonic lineages, but random X inactivation occurs in the embryo proper. In male (XY) embryos, which inherit only a maternal X chromosome, no silencing occurs through these mechanisms.