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      X-Chromosome Dosage Modulates Multiple Molecular and Cellular Properties of Mouse Pluripotent Stem Cells Independently of Global DNA Methylation Levels

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          Summary

          Reprogramming female mouse somatic cells into induced pluripotent stem cells (iPSCs) leads to X-chromosome reactivation. The extent to which increased X-chromosome dosage (X-dosage) in female iPSCs compared with male iPSCs leads to differences in the properties of iPSCs is still unclear. We show that chromatin accessibility in mouse iPSCs is modulated by X-dosage. Specific sets of transcriptional regulator motifs are enriched in chromatin with increased accessibility in XX or XY iPSCs. The transcriptome, growth and pluripotency exit are also modulated by X-dosage in iPSCs. To understand how increased X-dosage modulates the properties of mouse pluripotent stem cells, we used heterozygous deletions of the X-linked gene Dusp9. We show that X-dosage regulates the transcriptome, open chromatin landscape, growth, and pluripotency exit largely independently of global DNA methylation. Our results provide insights into how gene dosage modulates the epigenetic and genetic mechanisms that regulate cell identity.

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          Highlights

          • X-chromosome dosage modulates the pluripotent chromatin accessibility landscape

          • Increased X-chromosome dosage slows down growth

          • Dusp9 heterozygous female ESCs display pluripotency exit delay

          Abstract

          Female mouse pluripotent stem cells have two active X chromosomes while male cells have only one. Using genome-wide transcription and open chromatin analyses, Pasque and colleagues show that female and male iPSCs adopt differences in transcription, open chromatin landscape, and cellular growth. These differences can be uncoupled from global DNA hypomethylation in female ESCs through Dusp9 heterozygous deletion.

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          Most cited references33

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          Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution.

          Ectopic expression of the four transcription factors Oct4, Sox2, c-Myc, and Klf4 is sufficient to confer a pluripotent state upon the fibroblast genome, generating induced pluripotent stem (iPS) cells. It remains unknown if nuclear reprogramming induced by these four factors globally resets epigenetic differences between differentiated and pluripotent cells. Here, using novel selection approaches, we have generated iPS cells from fibroblasts to characterize their epigenetic state. Female iPS cells showed reactivation of a somatically silenced X chromosome and underwent random X inactivation upon differentiation. Genome-wide analysis of two key histone modifications indicated that iPS cells are highly similar to ES cells. Consistent with these observations, iPS cells gave rise to viable high-degree chimeras with contribution to the germline. These data show that transcription factor-induced reprogramming leads to the global reversion of the somatic epigenome into an ES-like state. Our results provide a paradigm for studying the epigenetic modifications that accompany nuclear reprogramming and suggest that abnormal epigenetic reprogramming does not pose a problem for the potential therapeutic applications of iPS cells.
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            The regulation of AP-1 activity by mitogen-activated protein kinases.

            M Karin (1995)
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              Pluripotent stem cells in disease modelling and drug discovery.

              Experimental modelling of human disorders enables the definition of the cellular and molecular mechanisms underlying diseases and the development of therapies for treating them. The availability of human pluripotent stem cells (PSCs), which are capable of self-renewal and have the potential to differentiate into virtually any cell type, can now help to overcome the limitations of animal models for certain disorders. The ability to model human diseases using cultured PSCs has revolutionized the ways in which we study monogenic, complex and epigenetic disorders, as well as early- and late-onset diseases. Several strategies are used to generate such disease models using either embryonic stem cells (ES cells) or patient-specific induced PSCs (iPSCs), creating new possibilities for the establishment of models and their use in drug screening.
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                Author and article information

                Contributors
                Journal
                Stem Cell Reports
                Stem Cell Reports
                Stem Cell Reports
                Elsevier
                2213-6711
                10 January 2019
                12 February 2019
                10 January 2019
                : 12
                : 2
                : 333-350
                Affiliations
                [1 ]KU Leuven – University of Leuven, Department of Development and Regeneration, Leuven Stem Cell Institute, Leuven Cancer Institute, Herestraat 49, 3000 Leuven, Belgium
                Author notes
                []Corresponding author juan.song@ 123456kuleuven.be
                [∗∗ ]Corresponding author vincent.pasque@ 123456kuleuven.be
                Article
                S2213-6711(18)30523-X
                10.1016/j.stemcr.2018.12.004
                6372905
                30639215
                c153c5fa-26f7-41bf-a13d-72d4b516d495
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 16 November 2018
                : 7 December 2018
                : 10 December 2018
                Categories
                Article

                x-chromosome reactivation,mouse pluripotent stem cells,pluripotency,dna methylation,chromatin accessibility,x-chromosome inactivation,x dosage,ips cells,dosage compensation

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