Molecular coupling of Tsix regulation and pluripotency

Pablo Navarro, Andrew Oldfield, Julie Legoupi, Nicola Festuccia, Agnès Dubois, Mikael Attia, Jon Schoorlemmer, Claire Rougeulle, Ian Chambers, and Philip Avner. Molecular coupling of Tsix regulation and pluripotency. Nature (2011), volume 468, 457-460 (18/11/2010). 2010, Vol. , p. -2010.

The reprogramming of X-chromosome inactivation during the acquisition of
pluripotency in-vivo and in-vitro1, is accompanied by the repression of Xist2, the trigger
of X-inactivation3, and the upregulation of its antisense counterpart Tsix4. We have
shown that key factors supporting pluripotency —Nanog, Oct4, and Sox2— bind within
Xist intron 1 in undifferentiated embryonic stem (ES) cells to repress Xist transcription5.
However, the relationship between transcription factors of the pluripotency network
and Tsix regulation has remained unclear5, 6. Here, we show that Tsix upregulation in ES
cells depends on the recruitment of the pluripotent marker Rex1, and of the
reprogramming-associated factors Klf4 and c-Myc, by the DXPas34 minisatellite
associated with the Tsix promoter. Upon deletion of DXPas34, binding of the three
factors is abrogated and the transcriptional machinery no longer efficiently recruited to
the Tsix promoter. Additional analyses including knock-down experiments further
demonstrate that Rex1 is critically important for efficient transcription elongation of
Tsix. Hence, distinct ES cell-specific complexes couple X-inactivation reprogramming
and pluripotency, with Nanog, Oct4 and Sox2 repressing Xist to facilitate the
reactivation of the inactive X, and Klf4, c-Myc and Rex1 activating Tsix to remodel Xist
chromatin7-10 and ensure random X-inactivation upon differentiation1. The holistic
scenario of Xist/Tsix regulation by pluripotent factors that we have identified suggests a
general direct governance of complex epigenetic processes by the machinery dedicated
to pluripotency.