Abstract
In somatic cells of female placental mammals, one of the two X chromosomes is transcriptionally silenced to accomplish an equal dose of X-encoded gene products in males and females. Initiation of random X chromosome inactivation (XCI) is thought to be regulated by X-encoded activators and autosomally encoded suppressors controlling Xist. Spreading of Xist RNA leads to silencing of the X chromosome in cis. Here, we demonstrate that the dose dependent X-encoded XCI activator RNF12/RLIM acts in trans and activates Xist. We did not find evidence for RNF12-mediated regulation of XCI through Tsix or the Xist intron 1 region, which are both known to be involved in inhibition of Xist. In addition, we found that Xist intron 1, which contains a pluripotency factor binding site, is not required for suppression of Xist in undifferentiated ES cells. Analysis of female Rnf12−/− knockout ES cells showed that RNF12 is essential for initiation of XCI and is mainly involved in the regulation of Xist. We conclude that RNF12 is an indispensable factor in up-regulation of Xist transcription, thereby leading to initiation of random XCI.
Highlights
X chromosome inactivation (XCI) in placental mammals is random with respect to the parental origin of the X chromosome that undergoes inactivation, during early embryonic development [1]
RNF12 acts in trans to activate XCI XCI is regulated by several cis elements, and Rnf12 is located in close proximity to Xist (,500 kb)
In ES cells, RNF12 exerts its main function in XCI Here, we present evidence that RNF12 is an essential activator of random XCI
Summary
X chromosome inactivation (XCI) in placental mammals is random with respect to the parental origin of the X chromosome that undergoes inactivation, during early embryonic development [1]. Imprinted XCI always targets the paternally inherited X chromosome (Xp), and is initiated during the early cleavage divisions [2,3,4]. In the inner cell mass (ICM) of the mouse blastocyst, the inactive X chromosome is reactivated, after which random XCI is initiated around 5.5 days of embryonic development. Two non-coding X-linked genes, Xist and Tsix, play a central role in the random XCI mechanism. Upon initiation of XCI, Xist is up-regulated on the future inactive X chromosome (Xi), and the transcribed RNA spreads along the X in cis, directly and indirectly recruiting chromatin modifying enzymes acting to establish the Xi [5,6,7]. Tsix is a negative regulator of Xist; the Tsix gene overlaps with Xist but is transcribed in the anti-sense direction [8,9]
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