Research highlights

Rnf12 and X inactivation

It has been hypothesized that there are X-linked activators of X-chromosome inactivation (XCI-activators) that function in dose-dependent activation of the Xist gene, which encodes a noncoding RNA transcript that spreads over the inactive X chromosome in female cells. Now, Joost Gribnau and colleagues report the first identification of an X-linked XCI-activator, the E3 ubiquitin ligase Rnf12 (Cell 139, 999–1011, 2009). The authors show that a transgene carrying Rnf12 triggered XCI in differentiating mouse embryonic stem (ES) cells. In male cells, transgenic expression of Rnf12 resulted in a cloud of Xist transcripts that accumulated on the X chromosome, whereas in female cells, there were two Xist clouds, indicating that both X chromosomes had been inactivated. Disruption of the open reading frame of Rnf12 rendered the transgene nonfunctional in inducing XCI, confirming the identity of Rnf12 as an XCI-activator. Expression studies revealed that the concentration of endogenous Rnf12 is higher in female cells than in male cells, and that it is expressed at XCI initiation during ES cell differentiation in accordance with its proposed role. Furthermore, targeted deletion of Rnf12 in female ES cells resulted in an 80% reduction of initiation of XCI during differentiation; this both confirms the function of Rnf12 and indicates the likely presence of additional XCI-activators. EN