Similar Datasets
Project description:Human induced Pluripotent Stem cells (iPSCs) can be generated by enforced-expression of OCT3/4, SOX2, KLF4 and c-MYC (OSKM) via intermediate state that is labeled with a surface antigen TRA-1-60. However the event during conversion of somatic cells to TRA-1-60 positive (+) fate by OSKM is still unclear. Here we show that TRA-1-60 (+) cells emerged from ESRG (+) cells with proliferation independent manner. Overcoming the proliferation pausing phase is crucial for further progression of reprogramming. Inactivation of RB pathway is associated with the expansion of early TRA-1-60 (+) cells. Indeed, extended RB activation drastically decreased the proportion of TRA-1-60 (+) cells with marked premature senescence. An RNA-binding protein LIN41 promotes the RB inactivation and facilitates reprogramming efficiency in early stage via post-transcriptional suppression of cycline dependent kinase inhibitor p21. This LIN41/p21/RB axis was invalidated in immortalized cells which showed a resistance to oncogene-induced senescence. Thus, LIN41- mediated RB inactivation promotes to bail out of transient quiescence as a major blockade in initial phase of reprogramming.
2018-04-10 | GSE89925 | GEO
Project description:Human induced Pluripotent Stem cells (iPSCs) can be generated by enforced-expression of OCT3/4, SOX2, KLF4 and c-MYC (OSKM) via intermediate state that is labeled with a surface antigen TRA-1-60. However the event during conversion of somatic cells to TRA-1-60 positive (+) fate by OSKM is still unclear. Here we show that TRA-1-60 (+) cells emerged from ESRG (+) cells with proliferation independent manner. Overcoming the proliferation pausing phase is crucial for further progression of reprogramming. Inactivation of RB pathway is associated with the expansion of early TRA-1-60 (+) cells. Indeed, extended RB activation drastically decreased the proportion of TRA-1-60 (+) cells with marked premature senescence. An RNA-binding protein LIN41 promotes the RB inactivation and facilitates reprogramming efficiency in early stage via post-transcriptional suppression of cycline dependent kinase inhibitor p21. This LIN41/p21/RB axis was invalidated in immortalized cells which showed a resistance to oncogene-induced senescence. Thus, LIN41- mediated RB inactivation promotes to bail out of transient quiescence as a major blockade in initial phase of reprogramming.
2017-12-01 | GSE89455 | GEO
Project description:Human induced Pluripotent Stem cells (iPSCs) can be generated by enforced-expression of OCT3/4, SOX2, KLF4 and c-MYC (OSKM) via intermediate state that is labeled with a surface antigen TRA-1-60. However the event during conversion of somatic cells to TRA-1-60 positive (+) fate by OSKM is still unclear. Here we show that TRA-1-60 (+) cells emerged from ESRG (+) cells with proliferation independent manner. Overcoming the proliferation pausing phase is crucial for further progression of reprogramming. Inactivation of RB pathway is associated with the expansion of early TRA-1-60 (+) cells. Indeed, extended RB activation drastically decreased the proportion of TRA-1-60 (+) cells with marked premature senescence. An RNA-binding protein LIN41 promotes the RB inactivation and facilitates reprogramming efficiency in early stage via post-transcriptional suppression of cycline dependent kinase inhibitor p21. This LIN41/p21/RB axis was invalidated in immortalized cells which showed a resistance to oncogene-induced senescence. Thus, LIN41- mediated RB inactivation promotes to bail out of transient quiescence as a major blockade in initial phase of reprogramming.
2018-04-10 | GSE89976 | GEO
Project description:Human induced Pluripotent Stem cells (iPSCs) can be generated by enforced-expression of OCT3/4, SOX2, KLF4 and c-MYC (OSKM) via intermediate state that is labeled with a surface antigen TRA-1-60. However the event during conversion of somatic cells to TRA-1-60 positive (+) fate by OSKM is still unclear. Here we show that TRA-1-60 (+) cells emerged from ESRG (+) cells with proliferation independent manner. Overcoming the proliferation pausing phase is crucial for further progression of reprogramming. Inactivation of RB pathway is associated with the expansion of early TRA-1-60 (+) cells. Indeed, extended RB activation drastically decreased the proportion of TRA-1-60 (+) cells with marked premature senescence. An RNA-binding protein LIN41 promotes the RB inactivation and facilitates reprogramming efficiency in early stage via post-transcriptional suppression of cycline dependent kinase inhibitor p21. This LIN41/p21/RB axis was invalidated in immortalized cells which showed a resistance to oncogene-induced senescence. Thus, LIN41- mediated RB inactivation promotes to bail out of transient quiescence as a major blockade in initial phase of reprogramming.
2018-04-10 | GSE89975 | GEO
Project description:Human induced Pluripotent Stem cells (iPSCs) can be generated by enforced-expression of OCT3/4, SOX2, KLF4 and c-MYC (OSKM) via intermediate state that is labeled with a surface antigen TRA-1-60. However the event during conversion of somatic cells to TRA-1-60 positive (+) fate by OSKM is still unclear. Here we show that TRA-1-60 (+) cells emerged from ESRG (+) cells with proliferation independent manner. Overcoming the proliferation pausing phase is crucial for further progression of reprogramming. Inactivation of RB pathway is associated with the expansion of early TRA-1-60 (+) cells. Indeed, extended RB activation drastically decreased the proportion of TRA-1-60 (+) cells with marked premature senescence. An RNA-binding protein LIN41 promotes the RB inactivation and facilitates reprogramming efficiency in early stage via post-transcriptional suppression of cycline dependent kinase inhibitor p21. This LIN41/p21/RB axis was invalidated in immortalized cells which showed a resistance to oncogene-induced senescence. Thus, LIN41- mediated RB inactivation promotes to bail out of transient quiescence as a major blockade in initial phase of reprogramming.
2018-04-10 | GSE90014 | GEO
Project description:Proliferation pause as an early blockade of human cellular reprogramming toward pluripotency
| PRJNA354325 | ENA
Project description:Members of the GATA protein family play important roles in lineage specification and transdifferentiation. Previous reports show that some members of the GATA protein family can also induce pluripotency in somatic cells by substituting for Oct4, a key pluripotency-associated factor. However, the mechanism linking lineage-specifying cues and the activation of pluripotency remains elusive. Here, we report that all GATA family members can substitute for Oct4 to induce pluripotency. We found that all members of the GATA family could inhibit the overrepresented ectodermal-lineage genes, which is consistent with previous reports indicating that a balance of different lineage-specifying forces is important for the restoration of pluripotency. A conserved zinc-finger DNA-binding domain in the C-terminus is critical for the GATA family to induce pluripotency. Using RNA-seq and ChIP-seq, we determined that the pluripotency-related gene Sall4 is a direct target of GATA family members during reprogramming and serves as a bridge linking the lineage-specifying GATA family to the pluripotency circuit. Thus, the GATA family is the first protein family of which all members can function as inducers of the reprogramming process and can substitute for Oct4. Our results suggest that the role of GATA family in reprogramming has been underestimated and that the GATA family may serve as an important mediator of cell fate conversion.
| S-EPMC4650575 | biostudies-literature
Project description:Enforced ectopic expression of a cocktail of pluripotency-associated genes such as Oct4, Sox2, Klf4 and c-Myc can reprogram somatic cells into induced pluripotent stem cells (iPSCs). The remarkable proliferation ability of iPSCs and their aptitude to redifferentiate into any cell lineage makes these cells a promising tool for generating a variety of human tissue in vitro. Yet, pluripotency induction is an inefficient process, as cells undergoing reprogramming need to overcome developmentally imposed epigenetic barriers. Recent work has shed new light on the molecular mechanisms that drive the reprogramming of somatic cells to iPSCs. Here, we present current knowledge on the transcriptional and epigenetic regulation of pluripotency induction and discuss how variability in epigenetic states impacts iPSCs' inherent biological properties.
| S-EPMC5514980 | biostudies-literature
Project description:The role of sirtuins (SIRTs) in cancer biology has been the focus of recent research. The similarities between underlying pathways involved in the induction of pluripotent stem cells and transformation of cancer cells revealed the role of SIRTs in cellular reprogramming. Seven SIRTs have been identified in mammals and downregulation of SIRT2 was found to facilitate the generation of primed pluripotent stem cells, such as human induced pluripotent stem cells. Herein, we evaluated the role of SIRT2 in naive pluripotent stem cell generation using murine cells. We found that absolute depletion of SIRT2 in mouse embryonic fibroblasts resulted in a notable reduction in reprogramming efficiency. SIRT2 depletion not only upregulated elements of the INK4/ARF locus, which in turn had an antiproliferative effect, but also significantly altered the expression of proteins related to the PI3K/Akt and Hippo pathways, which are important signaling pathways for stemness. Thus, this study demonstrated that SIRT2 is required for cellular reprogramming to naive states of pluripotency in contrast to primed pluripotency states.
| S-EPMC6117269 | biostudies-literature
Project description:Although transcriptional regulation of stem cell pluripotency and differentiation has been extensively studied, only a small number of studies have addressed the roles for posttranslational modifications in these processes. A key mechanism of posttranslational modification is ubiquitination by the ubiquitin-proteasome system (UPS). Here, using shotgun proteomics, we map the ubiquitinated protein landscape during embryonic stem cell (ESC) differentiation and induced pluripotency. Moreover, using UPS-targeted RNAi screens, we identify additional regulators of pluripotency and differentiation. We focus on two of these proteins, the deubiquitinating enzyme Psmd14 and the E3 ligase Fbxw7, and characterize their importance in ESC pluripotency and cellular reprogramming. This global characterization of the UPS as a key regulator of stem cell pluripotency opens the way for future studies that focus on specific UPS enzymes or ubiquitinated substrates.
| S-EPMC3549668 | biostudies-literature