Much of the mechanism of X chromosome inactivation has been GSK2118436 extensively studied and well characterized, including understanding the role of the antisense inhibitor, Tsix, to the proteins recruited to maintain the chromosome-wide inactivation, and the DNA–RNA–protein interactions that maintain X inactivation [ 4, 5, 6, 7 and 8]. However, a recent breakthrough was made in understanding how Xist is able to spread along the length of the entire chromosome without silencing other chromosomes or active areas of the X chromosome. Engreitz et al. using

1054 tiled probes to the 17-kb Xist transcript, pulled down unique sequences of genomic DNA bound to Xist at five time points during differentiation as Xist becomes induced. After ruling out the role of sequence motifs with Xist-recruiting ability, they found that the initial DNA sites bound by Xist were spatially proximal (based on Hi-C data) to the Xist locus [ 9••]. These results support a model that Xist spreads along the length of the chromosome by binding to distal sites that are spatially organized close to the newly transcribed Xist RNA. CHIR99021 By being able to modify chromatin structure at these regions, Xist is able to spread to newly silenced regions of the genome. Furthermore, regions that escape XCI are able to loop out and remain active while still permitting spatial spread of Xist. Since much more of the genome escapes XCI in humans

compared to mouse, it will be interesting to determine if this mechanism is conserved in humans. Other work has identified a new long non-coding RNA, XACT, specifically in human pluripotent stem cells [ 10••]. While not expressed in mice, XACT coats the active X chromosome and, in the absence of XIST, coats both chromosomes. Perhaps this reflects a human-specific mechanism by which cells prevent silencing of both X

chromosome, instead of, as in mouse, using TSIX as an antisense repressor. It is known that the human TSIX RNA has significantly less complementarity to human XIST than mouse Tsix and Xist, and its ability to act as an effective suppressor in this way has been questioned [ 11 and 12]. Prostatic acid phosphatase This paper begins to shed light on human specific aspects of XCI that may underlie the mechanistic differences between mouse and human. Finally, two other studies provide additional pieces of the mechanistic puzzle. First is evidence for the role of Jarid2 in recruiting PRC2 to Xist RNA in helping to mediate inactivation [ 13•]. The second is the surprising finding that the first intron of Xist seems dispensable for Xist expression and normal function during XCI in stem cells and during development, despite the fact that the region exhibits strong pluripotency factor binding [ 14•]. Taken together these mechanistic results illustrate that there is still much to learn about XCI in both humans and mice. The role of the X chromosome in cancer has been well documented but much data is only correlational [15, 16, 17 and 18].