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• W3083525614 abstract "In this issue of Cell Stem Cell, An et al., 2020An C. Feng G. Zhang J. Cao S. Wang Y. Wang N. Lu F. Zhou Q. Wang H. Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation.Cell Stem Cell. 2020; 27: 482-497Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar provide a model to study human X chromosome inactivation. They followed X chromosome activity and traced cellular heterogeneity in naive hESCS, showed that it is caused by incomplete blockade of FGF-signaling, and in doing so isolated cells resembling pre-implantation epiblasts. In this issue of Cell Stem Cell, An et al., 2020An C. Feng G. Zhang J. Cao S. Wang Y. Wang N. Lu F. Zhou Q. Wang H. Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation.Cell Stem Cell. 2020; 27: 482-497Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar provide a model to study human X chromosome inactivation. They followed X chromosome activity and traced cellular heterogeneity in naive hESCS, showed that it is caused by incomplete blockade of FGF-signaling, and in doing so isolated cells resembling pre-implantation epiblasts. X chromosome inactivation (XCI) is an epigenetic mechanism of dosage compensation between the two sexes in mammals, which leads to the lifelong transcriptional silencing of one randomly chosen X chromosome in females. XCI is triggered by the XIST long noncoding RNA, which recruits a series of co-factors including RNA and chromatin modifiers, to convert a euchromatic, active X chromosome (Xa) into a heterochromatic, inactive version (Xi) (Loda and Heard, 2019Loda A. Heard E. Xist RNA in action: Past, present, and future.PLoS Genet. 2019; 15: e1008333Crossref PubMed Scopus (49) Google Scholar). XCI has been extensively studied in mice, largely using mouse embryonic stem cells (mESCs), which are in a naive state of pluripotency with two Xa. mESCs recapitulate random XCI upon differentiation, thus faithfully modeling what happens in vivo following implantation. In contrast, most human embryonic stem cells (hESCs), while derived from pre-implantation blastocysts, feature molecular properties of the post-implantation epiblasts that have already undergone XCI. They thus cannot be employed to study the chain of events leading to X chromosome repression in humans, which likely differs from that in mouse. Indeed, both Xs are transcriptionally active yet express XIST in human female pre-implantation blastocysts, indicating that XCI displays species-specific characteristics in mammals (Patrat et al., 2020Patrat C. Ouimette J.F. Rougeulle C. X chromosome inactivation in human development.Development. 2020; 147: dev183095Crossref PubMed Scopus (16) Google Scholar). Several culture conditions have been recently developed to reset primed hESCs toward a naive state of pluripotency and to model human pre-implantation development. However, naive hESC populations are heterogenous regarding XCI. Both Xs are active in most cells but only a small subset express XIST bi-allelically (Sahakyan et al., 2017Sahakyan A. Kim R. Chronis C. Sabri S. Bonora G. Theunissen T.W. Kuoy E. Langerman J. Clark A.T. Jaenisch R. Plath K. Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation.Cell Stem Cell. 2017; 20: 87-101Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar; Vallot et al., 2017Vallot C. Patrat C. Collier A.J. Huret C. Casanova M. Liyakat Ali T.M. Tosolini M. Frydman N. Heard E. Rugg-Gunn P.J. Rougeulle C. XACT Noncoding RNA Competes with XIST in the Control of X Chromosome Activity during Human Early Development.Cell Stem Cell. 2017; 20: 102-111Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). Naive hESCs were moreover reported to undergo skewed XCI upon re-priming (Sahakyan et al., 2017Sahakyan A. Kim R. Chronis C. Sabri S. Bonora G. Theunissen T.W. Kuoy E. Langerman J. Clark A.T. Jaenisch R. Plath K. Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation.Cell Stem Cell. 2017; 20: 87-101Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). In this issue of Cell Stem Cell, An et al., 2020An C. Feng G. Zhang J. Cao S. Wang Y. Wang N. Lu F. Zhou Q. Wang H. Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation.Cell Stem Cell. 2020; 27: 482-497Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar investigated the source of such heterogeneity in naive hESCs and linked it to a persistent Fibroblast Growth Factor (FGF) signaling caused by autocrine FGF2. An et al., 2020An C. Feng G. Zhang J. Cao S. Wang Y. Wang N. Lu F. Zhou Q. Wang H. Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation.Cell Stem Cell. 2020; 27: 482-497Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar elegantly exploited a sensor line in which fluorescent GFP and tdTomato reporter genes are individually knocked in into each allele of MeCp2, which is an X-linked gene subject to XCI (Xa-GFP; Xi-tdTomato) (Theunissen et al., 2016Theunissen T.W. Friedli M. He Y. Planet E. O’Neil R.C. Markoulaki S. Pontis J. Wang H. Iouranova A. Imbeault M. et al.Molecular Criteria for Defining the Naive Human Pluripotent State.Cell Stem Cell. 2016; 19: 502-515Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). Using this, they monitored the activity of both X chromosomes in female hESCs. Since primed hESCs are in a post-XCI state, the starting population was 100% GFP+. Upon resetting toward the naive state using the 5iLA culture medium, which contains a cocktail of small-molecule inhibitors targeting several signaling pathways (Theunissen et al., 2014Theunissen T.W. Powell B.E. Wang H. Mitalipova M. Faddah D.A. Reddy J. Fan Z.P. Maetzel D. Ganz K. Shi L. et al.Systematic identification of culture conditions for induction and maintenance of naive human pluripotency.Cell Stem Cell. 2014; 15: 471-487Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar), cells rapidly became GFP+/tdTomato+, indicating the rapid reactivation of the Xi. Xi reactivation was confirmed at the level of the whole chromosome and also by the use of other cell lines and resetting methods. However, most cells displayed mono-allelic XIST expression, as previously reported (Sahakyan et al., 2017Sahakyan A. Kim R. Chronis C. Sabri S. Bonora G. Theunissen T.W. Kuoy E. Langerman J. Clark A.T. Jaenisch R. Plath K. Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation.Cell Stem Cell. 2017; 20: 87-101Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar; Vallot et al., 2017Vallot C. Patrat C. Collier A.J. Huret C. Casanova M. Liyakat Ali T.M. Tosolini M. Frydman N. Heard E. Rugg-Gunn P.J. Rougeulle C. XACT Noncoding RNA Competes with XIST in the Control of X Chromosome Activity during Human Early Development.Cell Stem Cell. 2017; 20: 102-111Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). Interestingly, two subpopulations of cells could be distinguished based on tdTomato fluorescence: one exhibiting a high tdTomato signal (HT) and a one with a low tdTomato signal (LT), suggesting differential MECP2:tdToamato promoter activity, which could be due to different levels of Xi reactivation. Further characterization of FACS-sorted HT and LT naive hESCs revealed that the HT subset shares molecular identity and X chromosome activity status with human pre-implantation epiblasts (Petropoulos et al., 2016Petropoulos S. Edsgärd D. Reinius B. Deng Q. Panula S.P. Codeluppi S. Plaza Reyes A. Linnarsson S. Sandberg R. Lanner F. Single-Cell RNA-Seq Reveals Lineage and X Chromosome Dynamics in Human Preimplantation Embryos.Cell. 2016; 165: 1012-1026Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar; Vallot et al., 2017Vallot C. Patrat C. Collier A.J. Huret C. Casanova M. Liyakat Ali T.M. Tosolini M. Frydman N. Heard E. Rugg-Gunn P.J. Rougeulle C. XACT Noncoding RNA Competes with XIST in the Control of X Chromosome Activity during Human Early Development.Cell Stem Cell. 2017; 20: 102-111Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). The transcriptome of HT naive hESCs was closer to E6 female pre-implantation epiblast than that of LT cells and they displayed higher expression of genes that are upregulated in naive ESC compared to primed, including NANOG, REX1, and TFCP2L1. In addition, in the HT population, 95% of the cells expressed XIST and X-linked genes in a bi-allelic fashion, in contrast to the LT population, in which XIST was expressed mono-allelically. In order to investigate the molecular pathways underlying the heterogeneity of pluripotency status within naive hESCs, An et al., 2020An C. Feng G. Zhang J. Cao S. Wang Y. Wang N. Lu F. Zhou Q. Wang H. Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation.Cell Stem Cell. 2020; 27: 482-497Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar focused on autocrine FGF signaling, whose blockade is required for naive mESC propagation. They, again, found differences between HT and LT cells in that HT cells expressed and secreted high levels of FGF4 and low levels of FGF2, while both FGF2 and FGF4 are expressed in LT cells. Their findings therefore suggested that the MEK inhibitor (PD0325901) contained in the 5iLA culture condition was sufficient to block MEK/ERK signaling induced by FGF4, but not when FGF2 is also present. This hypothesis was validated by supplementing FGF2 to the 5iLA culture medium of HT naive hESCs. This induced a rapid change in reporter expression, with the tdTomato signal dropping in most of the cells, accompanied by a switch from bi- to mono-allelic XIST expression. Conversely, the introduction of an additional FGF signaling inhibitor, SU5402, to LT cell culture medium reinstated a homogeneous HT population and confirmed that spurious FGF signaling yields heterogenous populations in terms of pluripotency and X activity status. The addition of SU5402 to 5iLA medium directly during the primed to naive conversion induced, however, substantial cell death, likely owing to the requirement of FGF2 for primed hESC pluripotency, therefore pointing to the need to adjust resetting protocols to directly obtain homogeneous populations of naive hESCs. The possibility of isolating pure populations based on fluorescent marker expression nevertheless set the stage for investigating XCI initiation during re-priming and differentiation. In contrast to previous reports (Sahakyan et al., 2017Sahakyan A. Kim R. Chronis C. Sabri S. Bonora G. Theunissen T.W. Kuoy E. Langerman J. Clark A.T. Jaenisch R. Plath K. Human Naive Pluripotent Stem Cells Model X Chromosome Dampening and X Inactivation.Cell Stem Cell. 2017; 20: 87-101Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar; Theunissen et al., 2016Theunissen T.W. Friedli M. He Y. Planet E. O’Neil R.C. Markoulaki S. Pontis J. Wang H. Iouranova A. Imbeault M. et al.Molecular Criteria for Defining the Naive Human Pluripotent State.Cell Stem Cell. 2016; 19: 502-515Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar), re-priming of HT naive hESCs was accompanied by random XCI in 60% of the cells, while the remaining 40% retained two active Xs. Similar observations were made in vivo, upon teratoma formation, when HT cells were injected in NOD-SCID mice. Further in vitro differentiation of pre-XCI re-primed hESCs by direct addition of fibroblast medium resulted in a non-random XCI. However, differentiation of the same cells through embryoid body formation recapitulated random XCI, demonstrating that the in vitro differentiation protocol strongly impacts XCI outcome, through yet unknown mechanisms. The field of human naive pluripotency is young, and it has been productive in the development of naive reprogramming techniques but faces the great challenge of benchmarking to a reference state, currently provided by in vitro generated human embryos (Boroviak and Nichols, 2017Boroviak T. Nichols J. Primate embryogenesis predicts the hallmarks of human naïve pluripotency.Development. 2017; 144: 175-186Crossref PubMed Scopus (70) Google Scholar). The findings of An et al., 2020An C. Feng G. Zhang J. Cao S. Wang Y. Wang N. Lu F. Zhou Q. Wang H. Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation.Cell Stem Cell. 2020; 27: 482-497Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar pave the way for further elaborations of culture conditions to sustain a homogeneous state of naive pluripotency in vitro, which constitutes a milestone for modeling early human development. Their results on X chromosome activity dynamics suggest that, in humans, XCI is established asynchronously, and that primed pluripotency can accommodate pre- and post-XCI states, at least in vitro. The in vivo relevance of these observations remains to be determined, even if asynchronous XCI has also been reported using an in vitro model of human implantation (Zhou et al., 2019Zhou F. Wang R. Yuan P. Ren Y. Mao Y. Li R. Lian Y. Li J. Wen L. Yan L. et al.Reconstituting the transcriptome and DNA methylome landscapes of human implantation.Nature. 2019; 572: 660-664Crossref PubMed Scopus (64) Google Scholar). Nevertheless, such a reporter system will likely illuminate the dark side of human XCI. Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome InactivationAn et al.Cell Stem CellJuly 15, 2020In BriefAn et al. show that incomplete blockage of endocrine FGF signaling causes heterogeneity of X chromosome status and pluripotent status in naive hESCs. Upon derivation of homogeneous population, naive hESC transcriptomes and X chromosome status resemble human preimplantation epiblast and can undergo random XCI upon differentiation. Full-Text PDF" @default.
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• W3083525614 title "Straight to the X: Modeling Human X Chromosome Inactivation in hESCs by FGF Signal Blockade" @default.
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