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Histone macroH 2 A 1 is concentrated in the inactive X chromosome of female preimplantation mouse embryos

X inactivation involves several changes in the structure or properties of the inactive X chromosome that are believed to play a role in the initiation and/or maintenance of transcriptional silencing (Heard et al., 1997). These include hypermethylation of CpG islands, hypoacetylation of core histones, asynchronous replication, and the accumulation of a large noncoding nuclear RNA from a gene called Xist. Xist RNA coats the inactive X chromosome in cis and is generally thought to be directly involved in the inactivation process, though how it mediates transcriptional silencing is unknown. We recently showed that the inactive X chromosome in adult female mammals is also characterized by a high concentration of the core histone macroH2A1.2, and can be distinguished in interphase nuclei as a large macroH2A-dense domain called a macrochromatin body (MCB) (Costanzi and Pehrson, 1998). MacroH2A1.2 is one of the three known macroH2A subtypes. Two subtypes, macroH2A1.1 and 1.2, are produced by alternate splicing of the macroH2A1gene (Pehrson et al., 1997; Rasmussen et al., 1999). The third subtype, macroH2A2.2, is produced from a separate gene (C. Costanzi and J. R. Pehrson, unpublished results). All three subtypes have a similar structure, consisting of an amino-terminal domain that closely resembles a full-length histone H2A followed by a large nonhistone domain that comprises 57% of the protein (Fig. 1A). The H2A domain appears to replace conventional H2A in a subset of nucleosomes and it was estimated that one in 30 nucleosomes in rat liver would contain macroH2A, assuming one macroH2A per nucleosome (Pehrson and Fried, 1992). The majority of the nonhistone region appears to have evolved from a gene of unknown function that originated prior to the appearance of eukaryotes (Pehrson and Fuji, 1998). On the basis of the homology of the nonhistone region to proteins involved in the replication of viral RNA, it was hypothesized that the nonhistone region may bind RNA and that the ocalization of macroH2A1 to the inactive X chromosome might be mediated by an interaction between the nonhistone region and Xist RNA (Pehrson and Fuji, 1998). A connection between Xist and macroH2A1 has been established in a mouse fibroblast model, in which deletion of part of the Xist locus from the inactive X chromosome leads to the loss of macroH2A1 association (Csankovszki et al., 1999). Two experimental systems have been used to examine the early events of X inactivation. One system uses female mouse embryonic stem (XX-ES) cells or embryonal carcinoma cells in vitro (Martin et al., 1978; Rastan and Robertson, 1985). In culture XX-ES cells undergo random X chromosome 2283 Development 127, 2283-2289 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 DEV4325