RNA and the Epigenetic Regulation of X Chromosome Inactivation

(Figure 1). In invertebrates, X-linked numerator and autosomally encoded denominator genes encode proteins which differ in relative abundance in XX versus XY or XO cells. A 2-fold difference in stoichiometry signals the production of master regulatory proteins, XO-lethal in Barbara Panning*‡ and Rudolf Jaenisch*† *Whitehead Institute for Biomedical Research Cambridge, Massachusetts 02142 †Department of Biology Massachusetts Institute of Technology Cambridge, Massachusetts 02139 C. elegans and Sex lethal in Drosophila, that initiate dosage compensation (reviewed in Cline and Meyer, 1996). Thus invertebrates distinguish between having Dosage compensation requires the fine tuning of tranone and two X chromosomes and additional X chromoscription of X-linked genes in response to mechanisms somes are lethal. In contrast mammals distinguish bethat detect a 2-fold difference inX chromosome number. tween having one and more than one X chromosome Though unique dosage compensation strategies are and can tolerate X chromosome aneuploidies. Mammals employed by different organisms, two important similariinactivate all X chromosomes in excess of one per dipties areapparent: dosage compensation is initiated early loid genome: all supernumerary X chromosomes in male in embryogenesis and stably propagated chromatin and female cells are inactivated, whereas in tetraploid modifications are used to modulate X-linked gene exfemales two X chromosomes are silenced and two repression. In C. elegans a complex of proteins involved in main active. Since it appears that a single X chromochromosome condensation and segregation assembles some per diploid genome is chosen to remain active on both X chromosomes in hermaphrodites and reduces (reviewed in Lee et al., 1996), we refer to the mechanism gene expression by a factor of two on each chromosome that mammals use to count X chromosomes as choice. (reviewed in Cline and Meyer, 1996). In D. melanogaster, The discovery of the human XIST gene and mouse Xist an RNA–protein complex organizes on the single X chrogene, have provided the first insight into the molecular mosome in male cells to stimulate transcription 2-fold mechanisms by which mammals detect 2-fold differrelative to each X chromosome in female cells (reviewed ences in X chromosome number and inactivate a single in Willard and Salz, 1997). In mammals, X-linked gene X chromosome in female cells. expression is equalized between thesexes by X inactivaX inactivation involves several steps: choice, initiation, tion, the transcriptional silencing of one X chromosome and spread. Choice between X chromosomes and initiain female cells (reviewed in Migeon, 1994). Thus, mamtion of X inactivation occur early in development, at the mals cope with a level of complexity that does not occur time when embryonic cells differentiate from totipotent in invertebrates: the localization of dosage compensalineages. X chromosome silencing is nucleated at and tion machinery to one of multiple X chromosomes. bidirectionally propagated from the X-inactivation cenMammals differ from flies and roundworms in the ter (Xic) (reviewed in Migeon, 1994). The Xist gene is located within the Xic and encodes a large, spliced, manner in which they count X chromosome number