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    • http www ncbi nlm nih

    2018-10-31

    (http://www.ncbi.nlm.nih.gov.eleen.top/geo/query/acc.cgi?token=rfopdesiwmqiepk&acc=GSE31413)
    Introduction The process of differentiation of mammalian embryonic stem cells (ESCs) involves an increasing restriction in proliferative capacity (Nichols and Smith, 2009), ending in protein phosphatase inhibitor exit in terminally differentiated cells (Coronado et al., 2013; Roccio et al., 2013; Ruiz et al., 2011). For a successful differentiation process, the embryonic transcriptional regulatory programs instructing proliferation should be coordinated with it. However, the regulation of cell cycle related genes during ESC differentiation remains unclear (Roccio et al., 2013). Despite recent progress (Pauklin and Vallier, 2013), whether a change in cell cycle regulation is in itself causative of a change in developmental potential is largely unknown. Instead, much work on cell cycle control in ESCs has focused on features likely associated with the establishment and maintenance of pluripotency. ESCs have very unusual cell cycle structure, characterized by a short cell division cycle time, truncated G1 and G2 phases, and a large proportion of cells in the S phase (Hindley and Philpott, 2013; Kapinas et al., 2013; Orford and Scadden, 2008; White and Dalton, 2005). Several studies report controversial observations about ESC cycle-specific cyclin-dependent kinase (CDK) activities (Ballabeni et al, 2011; Neganova et al. 2009; Sela et al. 2012). More broadly, several surveillance mechanisms handling genome stability and cell cycle progression are known to operate differently in ESCs (Kapinas et al. 2013; Hussein et al. 2013; Neganova et al., 2011; Becker et al., 2010). The most notable example of this unconventional behavior is the overruling of the restriction (R) point, which is thought to shield ESCs from extrinsic differentiation cues operating during early G1 and to allow ESCs to execute full proliferation (Orford and Scadden, 2008; Sage, 2012; Calder et al., 2013). Supporting this observation, acquisition of the R point control, presumably through the activation of the retinoblastoma-related family of proteins, is an early event in ESC differentiation (Ruiz et al., 2011; Hindley and Philpott, 2013). Moreover, recent advances support the notion that in ESCs the subnuclear reorganization of transcription during cell proliferation is different from that in differentiated cells (Meuleman et al., 2013; Aoto et al., 2006). Importantly, the unusual cell cycle has also been shown to positively correlate with the pluripotent state, although the molecular mechanisms are not fully understood; for instance, several experiments linked Oct-4, Nanog and Myc to CDKs and their inhibitors (Singh and Dalton, 2009) and to chromosome segregation factors (Nitzsche et al., 2011). Additional evidence that the unconventionally fast cell cycle kinetics in ESCs is associated with their pluripotent state comes from the loss of this behavior upon differentiation (Calder et al., 2013; White and Dalton, 2005) and the reacquisition of it upon reprogramming (Ghule et al., 2011; Egli et al.; 2008). Despite these advances, an unbiased genome-wide dissection of the relationship between the programs of cell cycle control and ESC differentiation would ideally require the observation of in vitro synchronously differentiating ESCs. Such an experiment is challenging for reasons including heterogeneous mitotic activities across an ESC colony (Jin et al, 2010), the exceedingly rapid ESC cycle and the reported biasing effects of ESC synchronization protocols on cell death and differentiation (Sela et al., 2012; Schneider and d\'Adda di Fagagna, 2012; Zhang et al., 2005). Hence, a preliminary in silico approach is an attractive possibility to identify and prioritize genes, pathways and processes for further analysis.
    Materials and methods
    Results
    Discussion A precise understanding of the relationship between the integrated regulation of ESC proliferation and differentiation might possibly be achieved through a quantitative distinction of the relative contributions of these two programs in the transcriptome variation measured in synchronously differentiating ESCs. However, the achievement of this experimental objective is hampered by several issues, which include the unusually rapid division of these cells (Kapinas et al. 2013), the heterogeneity of cell cycle profiles in self-renewal ESCs and the inefficiency of the synchronization protocols affected by side-effects and by cell death (Jin et al., 2010). Therefore, to shed light on the possibility that transcriptome variations during the cell cycle is systematically coordinated with those promoting ESC transition from self-renewal to differentiation, we devised an in silico approach involving meta-analysis of multiple datasets of in vitro transcriptome data independently measured in synchronously dividing cells or in differentiating ESCs. First we attained a high-quality resource of fate-specific differentially regulated genes in in vitro human ESC differentiation by taking advantage of synthesized results from meta-analysis of previously unconnected datasets. The cell cycle periodically regulated genes were acquired from previous analysis of human cell cycle transcriptome data in somatic cell culture models. Such data represent certainly an approximation of the cell cycle in ESCs. Since a systematic assay of cell cycle transcriptome changes in ESCs is not available, the PER genes, albeit clearly imperfect, are used as a proxy to derive potential, general relationships between the cell cycle and differentiation. We showed that the genes oscillating during the cell cycle overlap with differentially regulated genes during in vitro ESC differentiation and we showed that the extent of this overlap is differentiation fate-specific. Overlapping genes are robust as they were confirmed in a variety of analyses and represent valuable candidates for future studies, as they can enable the transition from ESC self-renewal to differentiation by shifting from oscillation during cell proliferation toward a polarized increase or decrease during differentiation.