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    • br Acknowledgments br Introduction Expression of a defined s

    2018-11-06


    Acknowledgments
    Introduction Expression of a defined set of transcription factors (OCT4, SOX2, KLF4, and c-MYC) reprograms human somatic cells to a pluripotent state, generating induced pluripotent stem cells (iPSCs) (Park et al., 2008b; Takahashi et al., 2007; Yu et al., 2007). iPSCs are similar to embryonic stem cells (ESCs) and are capable of indefinite self-renewal and differentiation into cells of all three germ layers. iPSCs also maintain the genomic composition of parental somatic cells and thus are considered as autologous cellular resources that are critical for cell therapy and in vitro disease modeling (Park et al., 2008a; Wu and Hochedlinger, 2011). Detailed genetic and epigenetic comparisons between iPSCs and ESCs, however, have shown that they are close but not identical (Chin et al., 2009). Reprogramming leaves reprogramming-specific epigenetic marks and produces copy number variation (Hussein et al., 2011; Lister et al., 2011). In addition, de novo mutations seem to accompany reprogramming and cause genetic alterations in iPSCs, although more in-depth analyses are needed before we can draw definite conclusions regarding the genetic changes in reprogramming (Abyzov et al., 2012; Gore et al., 2011). Reprogramming affects the X chromosome status in female cells. During early development, one of the active X chromosomes in the inner cell mass (ICM) cells of the buy LCL161 undergoes random X chromosome inactivation (XCI) when ICM cells differentiate into epiblast cells (Mak et al., 2004). Only cells that are committed to developing as primordial germ cells (PGCs) start to reactivate the inactive X chromosome during migration to the genital ridge. In contrast, somatic cells maintain the inactive X chromosome throughout their life (de Napoles et al., 2007). Murine ESCs derived from ICM cells are considered to be in a naive state, and there are two active X chromosomes in female ESCs (Hanna et al., 2010). The X chromosome status in murine female iPSCs is indistinguishable from that in murine ESCs. Reprogramming activates the inactive X chromosome to produce iPSCs with two active X chromosomes (Maherali et al., 2007). Human ESCs are presumed to be derived from the epiblast cells of the embryo and have one inactive X chromosome. However, successful derivation of human ESCs with two active X chromosomes suggested that human ESCs are counterparts of ICM cells as well, but are prone to undergo XCI unless they are maintained in a pristine physiological condition, including a hypoxic oxygen concentration and no oxidative stress (Diaz Perez et al., 2012; Lengner et al., 2010). Thus, most human ESCs were reported to carry only one active X chromosome. In-depth studies on female human ESCs categorized them into three classes according to their X chromosome status (Kim et al., 2011; Lessing et al., 2013). Class I female human ESCs have two active X chromosomes, like murine ESCs, and show neither H3K27me3 nor XIST foci. When differentiated, class I ESCs undergo random XCI and form H3K27me3 foci and a XIST cloud. Spontaneous inactivation of one of the two X chromosomes in class I ESCs results in the formation of H3K27me3 and XIST foci, leading to the conversion of class I to class II cells. Class II ESCs maintain the inactive X chromosome after differentiation. However, the inactive X chromosome in class II ESCs is reversible and becomes reactivated with treatment of HDAC inhibitors (Diaz Perez et al., 2012). Continuous long-term passaging of H3K27me3 foci-positive class II ESCs triggers them to become H3K27me3 foci-negative class III ESCs. Although they are negative for H3K27me3 foci and XIST expression, class III ESCs carry one inactive X chromosome whose status seems to be permanent, and do not show H3K27me3 foci upon differentiation (Diaz Perez et al., 2012). As in the case of human ESCs, female iPSCs seem to have only one active X chromosome because they retain the inactive X chromosome (Tchieu et al., 2010). However, some groups, including ours, have found that iPSCs with two active X chromosomes can be generated via reprogramming (Kim et al., 2011; Marchetto et al., 2010; Tomoda et al., 2012). Others found that reprogramming does not reactivate the inactive X chromosome, and instead the unstable inactive X chromosome undergoes epigenetic erosion, producing class III iPSCs (Mekhoubad et al., 2012). The female iPSCs that have lost XIST expression seem to be less desirable cells for cell therapy or disease modeling because XIST loss is highly correlated with upregulation of X-linked oncogenes, which leads to a high growth rate and poor differentiation (Anguera et al., 2012). A recent study showed that high expression of leukemia inhibitory factor (LIF) facilitates the derivation of iPSCs with two active X chromosomes (Tomoda et al., 2012). The difference in X chromosome status in iPSCs among different labs suggests that the X chromosome is not in a stable state in current culture conditions.