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LincU Preserves Naive Pluripotency by Restricting ERK Activity in Embryonic Stem Cells [overexpression]

ABSTRACT: While the functional roles of long non-coding RNAs (lncRNAs) have been increasingly identified, few lncRNAs that control the naive state of embryonic stem cells (ESCs) are known. Here, we report a naive-state-associated lncRNA, lincU, which is intrinsically activated by NANOG in naive mESCs. LincU-deficient mESCs exhibit a primed-like pluripotent state and potentiate the transition from naive state to primed state, whereas ectopic lincU expression maintains mESCs in the naive state. Mechanistically, we demonstrate that lincU directly binds and stabilizes the DUSP9 protein, an ERK-specific phosphatase, and then constitutively inhibits the ERK1/2 signaling pathway, which critically contributes to maintenance of the naive state. Importantly, we reveal the functional role of lincU to be evolutionarily conserved in human. Our findings thus unveil lincU as a conserved lncRNA that intrinsically restricts MAPK/ERK activity and maintains the naive state of ESCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE107417 | GEO | 2018/06/20

REPOSITORIES: GEO

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LincU Preserves Naive Pluripotency by Restricting ERK Activity in Embryonic Stem Cells [knockdown]

Project description:While the functional roles of long non-coding RNAs (lncRNAs) have been increasingly identified, few lncRNAs that control the naive state of embryonic stem cells (ESCs) are known. Here, we report a naive-state-associated lncRNA, lincU, which is intrinsically activated by NANOG in naive mESCs. LincU-deficient mESCs exhibit a primed-like pluripotent state and potentiate the transition from naive state to primed state, whereas ectopic lincU expression maintains mESCs in the naive state. Mechanistically, we demonstrate that lincU directly binds and stabilizes the DUSP9 protein, an ERK-specific phosphatase, and then constitutively inhibits the ERK1/2 signaling pathway, which critically contributes to maintenance of the naive state. Importantly, we reveal the functional role of lincU to be evolutionarily conserved in human. Our findings thus unveil lincU as a conserved lncRNA that intrinsically restricts MAPK/ERK activity and maintains the naive state of ESCs.

2018-06-20 | GSE107416 | GEO

Comparison of transcriptional profiles between naive, primed and ground state pluripotency in mouse embryonic stem cells of the same genetic background

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Project description:Pluripotent stem cells can give rise to the three embryonic germ layers and the characterization of their properties is crucial to exploit their therapeutic potential. Mouse embryonic stem cells (mESCs) are isolated and usually maintained in vitro in a primed state that resembles the post-implantation epiblast features. Furthermore, primed mESCs can be de-differentiated to a naive state that resembles the pre-implantation inner cell mass (ICM). Cell differentiation or genotoxic stress, among others, can alter DNA replication, which is a flexible process able to adapt to different cellular contexts. Here, we demonstrate that primed-to-naive mESC reprogramming triggers replication fork slowdown, increased fork asymmetry and a compensatory activation of dormant origins. Using iPOND (“isolation of proteins on nascent DNA”) coupled to mass spectrometry we have characterized the changes in replisome composition between naive and primed mESCs. Several DNA repair factors, including MRE11 nuclease, are enriched in naive mESCs forks, while factors involved in ubiquitin-dependent protein metabolism are enriched in primed mESC forks. We report that primed-to-naive mESC de-differentiation promotes recruitment of MRE11 to the forks in response to transcription-replication conflicts, underlying the DNA replication rewiring required for efficient mESC reprogramming.

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Trincr1 RNA pull down MS in mESC

Project description:Long noncoding RNAs (lncRNAs) have emerged as important components of gene regulatory network in embryonic stem cells (ESCs). However, the function and molecular mechanism of lncRNAs are still largely unknown. Here we identified Trincr1 (TRIM71 interacting long noncoding RNA 1) lncRNA that regulates the FGF/ERK signaling and self-renewal of ESCs. Trincr1 is exported by THOC complex to cytoplasm where it binds and represses TRIM71, leading to the downregulation of SHCBP1 protein. Knocking out Trincr1 leads to the upregulation of phosphorylated ERK and ERK pathway target genes and the decrease of ESC self-renewal, while knocking down Trim71 completely rescues the defects of Trincr1 knockout. Furthermore, ectopic expression of Trincr1 represses FGF/ERK signaling and the self-renewal of neural progenitor cells. Together, this study reveals more regulators in FGF/ERK signaling pathway and highlights lncRNA as an important player in cell signaling network to coordinate cell fate specification.

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Project description:Embryonic stem cells (ESCs) of mice and humans have distinct molecular and biological characteristics, raising the question whether an earlier ‘naive’ state of pluripotency may exist in humans. Here we took a systematic approach to identify small molecules that support autonomous self-renewal of naive human ESCs based on maintenance of endogenous OCT4 distal enhancer activity, a molecular signature of ground state pluripotency. Iterative chemical screening identified a combination of five kinase inhibitors that induces and maintains OCT4 distal enhancer activity when applied directly to conventional human ESCs. These inhibitors generate a homogeneous population of human pluripotent stem cells in which transcription factors associated with the ground state of pluripotency are highly upregulated. Comparison with previously reported naive human ESCs indicates that our kinase inhibitor cocktail captures a novel pluripotent state in humans that closely resembles mouse ESCs. ChIP-seq data from human embryonic stem cells in naive and primed conditions were generated by deep sequencing using Illumina Hi-Seq 2000.

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Systematic Identification of Defined Conditions for Induction and Maintenance of Naive Human Pluripotency [expression]

Project description:Embryonic stem cells (ESCs) of mice and humans have distinct molecular and biological characteristics, raising the question whether an earlier ‘naive’ state of pluripotency may exist in humans. Here we took a systematic approach to identify small molecules that support autonomous self-renewal of naive human ESCs based on maintenance of endogenous OCT4 distal enhancer activity, a molecular signature of ground state pluripotency. Iterative chemical screening identified a combination of five kinase inhibitors that induces and maintains OCT4 distal enhancer activity when applied directly to conventional human ESCs. These inhibitors generate a homogeneous population of human pluripotent stem cells in which transcription factors associated with the ground state of pluripotency are highly upregulated. Comparison with previously reported naive human ESCs indicates that our kinase inhibitor cocktail captures a novel pluripotent state in humans that closely resembles mouse ESCs. Expression analysis was performed on two groups of human ESC samples: WIBR2 (P12 and P14), WIBR3 (P9) and WIN1 (P10) human ESCs derived in our optimized naive medium (5i/L/A or 6i/L/A, as indicated), and parental WIBR2 and WIBR3 human ESCs in primed human ESC medium.

2014-07-16 | E-GEOD-59430 | biostudies-arrayexpress

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Project description:The combination of Wnt pathway activation by the GSK3 inhibitor and ERK pathway inhibition by the MEK inhibitor, which is known as 2i is a well-established method to maintain mouse embryonic stem cell (mESC) self-renewal. Here we show that Activin A also has the ability to promote naive pluripotency of mESCs when combined with the MEK inhibitor PD0325901. mESCs were efficiently propagated in a medium containing both Activin A and the MEK inhibitor (PD0325901). mESCs cultured in Activin+PD retained a pluripotency state that expresses high levels of naive pluripotency-related transcription factors and is able to differentiate into three germ layers under appropriate conditions. They also showed naive pluripotency features, including the preferential usage of the Oct4 distal enhancer and the self-renewal response to Wnt pathway activation. Our finding provides another way to maintain the naive pluripotency state and reveals a role of Activin/Nodal/TGF-β signaling in stabilizing self-renewal gene regulatory networks in mESCs. To compare the gene expression patterns of naive and primed pluripotency states and their responses to Wnt and ERK1/2 MAPK pathway, we performed genome-wide gene expression analysis of mESCs and EpiLCs, and those treated with Wnt pathway activator alone or Wnt pathway activator combined with ERK1/2 MAPK pathway inhibitior.

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Project description:Mouse embryonic stem cells (mESCs) are in naive pluripotency that represents the ground state of development, from which all cells in the mouse embryo are derived. In contrast, human embryonic stem cells (hESCs) are in a primed state of pluripotency with many different properties. Despite intense efforts to generate naive human pluripotent stem cells (hPSCs), it has not been possible to derive naive hPSCs without relying on transgene overexpression or chemicals. Here, we show that a transient treatment with Torin1, a selective inhibitor of mTOR, converted hPSCs from primed to naive pluripotency. The naive hPSCs were maintained in the same condition as mESCs in defined media with 2iLI (MEK inhibitor, GSK3b inhibitor, LIF and Insulin). Like mESCs, they exhibited high clonal efficiency, rapid cell proliferation, active mitochondrial respiration, X chromosome activation, DNA hypomethylation, and transcriptomes similar to those of human blastocysts than primed hESCs. Most importantly, the naive hPSCs significantly contributed to mouse embryos when transferred to mouse blastocysts. mTor inhibition induced nuclear translocation of TFE3, a critical transcription factor at the interplay of autophagy and pluripotency. TFE3 with mutated nuclear localization signal blocked the conversion from primed to naive pluripotency. It appears that by mimicking diapause at the cellular level, naive pluripotency in human can be readily attained from primed hPSCs, thus establishing the unified ground state of pluripotency in mammals.

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Human Naive Pluripotency Attained by Transient Inhibition of mTor

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