Reactivation of the inactive X chromosome in development and reprogramming
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Cellular and Molecular Life Sciences
REVIEW
Reactivation of the inactive X chromosome in development and reprogramming Tatsuya Ohhata • Anton Wutz
Received: 15 June 2012 / Revised: 26 August 2012 / Accepted: 17 September 2012 Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract In mammals, one of the two X chromosomes of female cells is inactivated for dosage compensation between the sexes. X chromosome inactivation is initiated in early embryos by the noncoding Xist RNA. Subsequent chromatin modifications on the inactive X chromosome (Xi) lead to a remarkable stability of gene repression in somatic cell lineages. In mice, reactivation of genes on the Xi accompanies the establishment of pluripotent cells of the female blastocyst and the development of primordial germ cells. Xi reactivation also occurs when pluripotency is established during the reprogramming of somatic cells to induced pluripotent stem cells. The mechanism of Xi reactivation has attracted increasing interest for studying changes in epigenetic patterns and for improving methods of cell reprogramming. Here, we review recent advances in the understanding of Xi reactivation during development and reprogramming and illustrate potential clinical applications. Keywords X chromosome inactivation Dosage compensation Mammalian development Reprogramming
Abbreviations Xic X inactivation center XCI X chromosome inactivation Xi Inactive X chromosome Xa Active X chromosome PGCs Primordial germ cells MSCI Meiotic sex chromosome inactivation Xm Maternally inherited X chromosome Xp Paternally inherited X chromosome H3K27me3 Histone H3 tri-methylated on lysine 27 HDAC Histone deacetylase PcG Polycomb group H4Ac Acetylated histone H4 5mC 5 methyl cytosine 5hmC 5 hydroxymethyl cytosine ICM Inner cell mass ES cells Embryonic stem cells EC Embryonic carcinoma cells EpiSCs Epiblast stem cells iPS cells Induced pluripotent stem cells EG cells Embryonic germ cells
Introduction T. Ohhata A. Wutz (&) Wellcome Trust and MRC Stem Cell Institute, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK e-mail: [email protected] Present Address: T. Ohhata (&) Department of Molecular Biology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan e-mail: [email protected]
The inactive X chromosome (Xi) was originally observed as a dense staining structure in the nucleus of female cat neurons [1]. Since the original observation, the Barr body has inspired studies and served as a ‘‘visual’’ model for a silent chromatin state within the mammalian cell nucleus. Over the last 50 years, the process of X inactivation has kept its secrets. Although tremendous progress has been made by a number of laboratories, the mechanism behind X inactivation in its entirety remains to be worked out. The
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complexity of the overall mechanism, which also involves pathways that are known to be important for developmental gene regulation, has cap
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