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Molecular coupling of Tsix regulation and pluripotency

机译：Tsix调节与多能性的分子偶联

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摘要

The reprogramming of X-chromosome inactivation during the acquisition of pluripotency in vivo and in vitro is accompanied by the repression of Xist, the trigger of X-inactivation, and the upre-gulation of its antisense counterpart Tsix. We have shown that key factors supporting pluripotency-Nanog, Oct4 and Sox2-bind within Xist intron 1 in undifferentiated embryonic stem cells (ESC) to repress Xist transcription. However, the relationship between transcription factors of the pluripotency network and Tsixregulation has remained unclear. Here we show that Tsix upregulation in embryonic stem 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 is no longer efficiently recruited to the Tsixpromoter. Additional analyses including knockdown experiments further demonstrate that Rexl is critically important for efficient transcription elongation of Tsix. Hence, distinct embryonic-stem-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 Rexl activating Tsix to remodel Xist chromatin and ensure random X-inactivation upon differentiation. The holistic pattern 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.
机译：在体内和体外获得多能性过程中，X染色体失活的重编程伴随着Xist的抑制，X失活的触发以及其反义对应物Tsix的上调。我们已经显示了在未分化的胚胎干细胞（ESC）中支持Xist内含子1内的多能性Nanog，Oct4和Sox2结合的关键因素，以抑制Xist转录。然而，多能网络的转录因子与Tsix调节之间的关系仍不清楚。在这里，我们显示胚胎干细胞中Tsix的上调取决于与Tsix启动子相关的DXPas34小卫星募集的多能性标记Rex1以及与重编程相关的因子Klf4和c-Myc。删除DXPas34后，将取消这三个因子的结合，并且转录机制不再有效地募集到Tsix启动子。包括敲除实验在内的其他分析进一步证明，Rex1对于Tsix的有效转录延伸至关重要。因此，不同的胚胎干细胞特异性复合物将X灭活重编程和多能性结合在一起，其中Nanog，Oct4和Sox2抑制Xist以促进非活性X的重新激活，而Klf4，c-Myc和Rexl激活Tsix以重塑Xist染色质。并确保分化后随机X灭活。我们已经确定的通过多能性因素对Xist / Tsix进行调控的整体模式表明，由专用于多能性的机制可以对复杂的表观遗传过程进行一般的直接治理。

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  • 来源
    《Nature》 |2010年第7322期|p.457-460|共4页
  • 作者

    Pablo Navarro; Andrew Oldfield; Julie Legoupi; Nicola Festuccia; Agnes Dubois; Mikael Attia; Jon Schoorlemmer; Claire Rougeulle; Ian Chambers; Philip Avner;

  • 作者单位

    Unite de Genetique Moleculaire Murine, URA 2578, Institut Pasteur, 75724 Paris Cedex 15, France Medical Research Council (MRC) Centre Development in Stem Cell Biology, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JQ, UK;

    rnUnite de Genetique Moleculaire Murine, URA 2578, Institut Pasteur, 75724 Paris Cedex 15, France UMR 7216 Epigenetique et Destin Cellulaire, CNRS/Universite Paris Diderot, Case 7042,75205 Paris Cedex 13, France;

    rnUnite de Genetique Moleculaire Murine, URA 2578, Institut Pasteur, 75724 Paris Cedex 15, France;

    rnMedical Research Council (MRC) Centre Development in Stem Cell Biology, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JQ, UK;

    rnUnite de Genetique Moleculaire Murine, URA 2578, Institut Pasteur, 75724 Paris Cedex 15, France;

    rnUnite de Genetique Moleculaire Murine, URA 2578, Institut Pasteur, 75724 Paris Cedex 15, France;

    rnARAID Foundation and Institute Aragones de Ciencias de la Salud, Departamento de Anatomia y Embriologia, Facultad de Veterinaria, 50013 Zaragoza, Spain;

    rnUnite de Genetique Moleculaire Murine, URA 2578, Institut Pasteur, 75724 Paris Cedex 15, France UMR 7216 Epigenetique et Destin Cellulaire, CNRS/Universite Paris Diderot, Case 7042,75205 Paris Cedex 13, France;

    rnMedical Research Council (MRC) Centre Development in Stem Cell Biology, Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JQ, UK;

    rnUnite de Genetique Moleculaire Murine, URA 2578, Institut Pasteur, 75724 Paris Cedex 15, France;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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