nature:Molecular coupling of Tsix regulation and pluripotency

argonaute

The reprogramming of X-chromosome inactivation during the/ g' K1 P4 k, w* A$ Y3 D
acquisition of pluripotency in vivo and in vitro1 is accompanied by0 M% w( N, p6 G6 a9 R
the repression of Xist2, the trigger of X-inactivation3, and the upregulation: Z& y! t5 V6 {) l, ^2 z# c
of its antisense counterpart Tsix4. We have shown that key
7 u# J( {$ z* k8 G7 i4 O; Lfactors supporting pluripotency—Nanog, Oct4 and Sox2—bind
/ Q$ w1 X/ m8 D6 ywithin Xist intron 1 in undifferentiated embryonic stem cells (ESC)0 S3 u, D; P+ p; b/ @! ^, Z  @  p
to repress Xist transcription5. However, the relationship between
# V. _, s7 o! g; W( }, y. V# L$ ktranscription factors of the pluripotency network andTsix regulation
  A; u% ]8 \2 h  Phas remained unclear5,6. Here we show that Tsix upregulation in0 v: P' L  z( p8 q' V
embryonic stem cells depends on the recruitment of the pluripotent
. u8 ^8 F( S& V7 b7 Tmarker Rex1, and of the reprogramming-associated factors Klf4 and
$ a' m/ b% o% ^' D% r2 F, @( V5 Gc-Myc, by the DXPas34 minisatellite associated with the Tsix promoter.  M! O: c" ~$ Y0 b: `$ ~
Upon deletion of DXPas34, binding of the three factors is7 I" o! ~* ^' X
abrogated and the transcriptional machinery is no longer efficiently
  P9 z! v6 F% x7 ]% L( W6 R8 K4 z9 mrecruited to the Tsix promoter.Additional analyses including knockdown, k& |* j/ Y, o: L* \6 }+ Q0 i
experiments furtherdemonstrate thatRex1 is critically important
$ D/ z/ X: _+ n/ j, x# D+ x4 yfor efficient transcription elongation of Tsix. Hence, distinct
+ q8 L) |, n( F, u# Uembryonic-stem-cell-specific complexes coupleX-inactivation reprogramming+ F% s8 A6 V) I4 W6 L  E4 a( n
and pluripotency, with Nanog, Oct4 and Sox2 repressing
6 h( ]2 @7 y& e6 m$ Y4 F  s( \: |# RXist to facilitate the reactivation of the inactive X, and Klf4, c-Myc( s2 J9 W$ W1 H6 g8 V8 m
and Rex1 activating Tsix to remodel Xist chromatin7–10 and ensure4 h/ n+ ]* x; Q0 q! [: u/ G
random X-inactivation upon differentiation1. The holistic pattern of
6 g) W) P7 m# o8 K: ?Xist/Tsix regulation by pluripotent factors that we have identified4 r# t, h  U( t
suggests a general direct governance of complex epigenetic processes) _, b" O' Y( z8 E, y
by the machinery dedicated to pluripotency.

arruhany

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