ESRG, a novel target of OCT4, maintains self-renewal and pluripotency of human pluripotent stem cells in collaboration with MCM2
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PROVIDER: PRJNA789184 | ENA |
REPOSITORIES: ENA
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Project description:Long non-coding RNA ESRG was first identified in our previous study, but its physiological function, regulatory and action mechanisms in human pluripotent stem cells (hPSCs) remain largely unexplored. Here, we found that ESRG is specifically and highly expressed in hPSCs, and its transcription is directly regulated by OCT4, suggesting that ESRG may be an integral component of the core regulatory circuit regulating the pluripotent state of hPSCs. Knockdown of ESRG induces hPSC differentiation, cell cycle arrest, and apoptosis. Mechanistically, ESRG binds to minichromosome maintenance protein 2 (MCM2), a replication-licensing factor, to sustain its steady-state level and nuclear translocation, safeguarding error-free DNA replication. Further study showed that inhibition of the interaction bewteen ESRG and MCM2 results in DNA damage and activation of p53 signaling pathway, ultimately deregulates deregulates pluripotency and self-renewal of hPSCs. In sum, our observations suggest that ESRG, as a novel target of OCT4, plays an essential role in maintaining the pluripotency and self-renewal of hPSCs in collaboration with MCM2 to suppress p53 signaling. These findings provide critical insights into the mechanisms underlying the maintenance of self-renewal and pluripotency in hPSCs.
2023-03-02 | GSE190957 | GEO
Project description:Elucidating the mechanism of self-renewal and pluripotency maintenance of human embryonic stem cells (hESCs) is of great significance in basic research and clinical applications. Long non-coding RNAs (lncRNAs) have been shown to play a key role in the self-renewal and pluripotency maintenance of hESCs. We previously reported that the lncRNA ESRG, which is highly expressed in undifferentiated hESCs, can interact with the replication licensing factor MCM2 and inhibit the p53 pathway to maintain the self-renewal and pluripotency of hPSCs. In addition to MCM2, RNA pull-down mass spectrometry showed that ESRG could also bind to other proteins, among which heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) attracted our attention. In this study, we show that HNRNPA1 can maintain self-renewal and pluripotency of hESCs. ESRG binds to and stabilizes HNRNPA1 protein through the ubiquitin-proteasome pathway. In addition, knockdown of ESRG or HNRNPA1 resulted in alternative splicing of TCF3, which originally and primarily encodes E12, to mainly encode E47 and inhibit CDH1 expression. HNRNPA1 could rescue the biological function changes of hESCs caused by ESRG knockdown or overexpression. Our results suggest that ESRG regulates the alternative splicing of TCF3 to affect CDH1 expression and maintain hESCs self-renewal and pluripotency by binding and stabilizing HNRNPA1 protein. This study lays a good foundation for exploring the new molecular regulatory mechanism by which ESRG maintains hESCs self-renewal and pluripotency.
2024-03-05 | GSE236745 | GEO
Project description:Oct4 is considered a master transcription factor for pluripotent cell self-renewal and embryo development. It primarily collaborates with other transcriptional factors or coregulators to maintain pluripotency. However, it is still unclear how Oct4 interacts with its partners. Here, we show that the Oct4 linker interface mediates competing and balanced Oct4 protein interactions which are crucial for maintaining pluripotency. Linker mutant ESCs maintain the key pluripotency genes expression, but show decreased expression of self-renewal genes and increased expression of differentiation genes which result in impaired ESCs self-renewal and early embryonic lethality. Linker mutation dose not affect Oct4 genomic binding and transactivation potential, but breaks the balanced Oct4 interactome. In mutant ESCs, the interaction between Oct4 and Klf5 was decreased, but interactions between Oct4 and Cbx1, Ctr9, Cdc73 were increased which disrupt the epigenetic state of ESCs. Overexpression of Klf5 or knockdown Cbx1, Cdc73 rescue the cellular phenotype of linker mutant ESCs by rebalancing Oct4 interactome indicating that different partners interact with Oct4 competitively. Thus, by showing how Oct4 interacts with different partners, we provide novel molecular insights to explain how Oct4 contributes to the maintenance of pluripotency.
2021-12-10 | PXD017456 | Pride
Project description:Human pluripotent stem cells (PSCs) express human endogenous retroviruses type-H (HERV-Hs), which exist more than a thousand copies on the human genome and frequently produce chimeric transcripts as long-non-coding RNAs (lncRNAs) fused with downstream neighbor genes. Previous studies showed that HERV-H expression is required for the maintenance of PSC identity, and the aberrant HERV-H expression attenuated neural differentiation potentials, but little is known what their roles are. In this study, therefore, we focused on ESRG, which is known as a PSC-related HERV-H-driven lncRNA. The global transcriptome data of various tissues and cell lines and quantitative expression analysis showed that ESRG expression is much higher than other HERV-Hs and tightly silenced after differentiation, letting us hypothesize its crucial role in human pluripotency. However, the loss of function by the complete excision of the entire ESRG gene body using a CRISPR/Cas9 platform revealed that ESRG is dispensable for the maintenance of primed and naïve pluripotent states. The loss of ESRG hardly affects the global gene expression of PSCs and differentiation potentials toward trilineage. Differentiated cells derived from ESRG knockout PSCs retained the potential to be reprogrammed into induced PSC (iPSC) by the forced expression of OCT3/4, SOX2, and KLF4. In conclusion, ESRG is dispensable for the maintenance and the recapturing of human pluripotency.
2021-05-11 | GSE156834 | GEO
Project description:ESRG regulates alternative splicing of TCF3 to maintain hESCs self-renewal and pluripotency
| PRJNA992127 | ENA
Project description:Human pluripotent stem cells (PSCs) express human endogenous retroviruses type-H (HERV-Hs), which exist more than a thousand copies on the human genome and frequently produce chimeric transcripts as long-non-coding RNAs (lncRNAs) fused with downstream neighbor genes. Previous studies showed that HERV-H expression is required for the maintenance of PSC identity, and the aberrant HERV-H expression attenuated neural differentiation potentials, but little is known what their roles are. In this study, therefore, we focused on ESRG, which is known as a PSC-related HERV-H-driven lncRNA. The global transcriptome data of various tissues and cell lines and quantitative expression analysis showed that ESRG expression is much higher than other HERV-Hs and tightly silenced after differentiation, letting us hypothesize its crucial role in human pluripotency. However, the loss of function by the complete excision of the entire ESRG gene body using a CRISPR/Cas9 platform revealed that ESRG is dispensable for the maintenance of primed and naïve pluripotent states. The loss of ESRG hardly affects the global gene expression of PSCs and differentiation potentials toward trilineage. Differentiated cells derived from ESRG knockout PSCs retained the potential to be reprogrammed into induced PSC (iPSC) by the forced expression of OCT3/4, SOX2, and KLF4. In conclusion, ESRG is dispensable for the maintenance and the recapturing of human pluripotency.
2021-05-11 | GSE159101 | GEO
Project description:Human pluripotent stem cells (PSCs) express human endogenous retroviruses type-H (HERV-Hs), which exist more than a thousand copies on the human genome and frequently produce chimeric transcripts as long-non-coding RNAs (lncRNAs) fused with downstream neighbor genes. Previous studies showed that HERV-H expression is required for the maintenance of PSC identity, and the aberrant HERV-H expression attenuated neural differentiation potentials, but little is known what their roles are. In this study, therefore, we focused on ESRG, which is known as a PSC-related HERV-H-driven lncRNA. The global transcriptome data of various tissues and cell lines and quantitative expression analysis showed that ESRG expression is much higher than other HERV-Hs and tightly silenced after differentiation, letting us hypothesize its crucial role in human pluripotency. However, the loss of function by the complete excision of the entire ESRG gene body using a CRISPR/Cas9 platform revealed that ESRG is dispensable for the maintenance of primed and naïve pluripotent states. The loss of ESRG hardly affects the global gene expression of PSCs and differentiation potentials toward trilineage. Differentiated cells derived from ESRG knockout PSCs retained the potential to be reprogrammed into induced PSC (iPSC) by the forced expression of OCT3/4, SOX2, and KLF4. In conclusion, ESRG is dispensable for the maintenance and the recapturing of human pluripotency.
2021-05-11 | GSE171849 | GEO
Project description:Human pluripotent stem cells (PSCs) express human endogenous retroviruses type-H (HERV-Hs), which exist more than a thousand copies on the human genome and frequently produce chimeric transcripts as long-non-coding RNAs (lncRNAs) fused with downstream neighbor genes. Previous studies showed that HERV-H expression is required for the maintenance of PSC identity, and the aberrant HERV-H expression attenuated neural differentiation potentials, but little is known what their roles are. In this study, therefore, we focused on ESRG, which is known as a PSC-related HERV-H-driven lncRNA. The global transcriptome data of various tissues and cell lines and quantitative expression analysis showed that ESRG expression is much higher than other HERV-Hs and tightly silenced after differentiation, letting us hypothesize its crucial role in human pluripotency. However, the loss of function by the complete excision of the entire ESRG gene body using a CRISPR/Cas9 platform revealed that ESRG is dispensable for the maintenance of primed and naïve pluripotent states. The loss of ESRG hardly affects the global gene expression of PSCs and differentiation potentials toward trilineage. Differentiated cells derived from ESRG knockout PSCs retained the potential to be reprogrammed into induced PSC (iPSC) by the forced expression of OCT3/4, SOX2, and KLF4. In conclusion, ESRG is dispensable for the maintenance and the recapturing of human pluripotency.
2021-05-11 | GSE171627 | GEO
Project description:Determination of the genome-wide distribution of the Mcm2-7 helicase by chromatin immunoprecipitation in the Drosophila Kc167 cell line at the beginning of S phase. Kc167 cells were arrested at the G1/S transition with hydroxyurea (HU). Goal was to evaluate changes in the genome-wide Mcm2-7 distribution throughout the cell cycle, and how this relates to the excess Mcm2-7 loaded onto chromatin in G1. ChIP-Chip of Mcm2-7 in HU compared to input genomic DNA. Biological Replicates: 2
2014-11-27 | E-GEOD-63680 | biostudies-arrayexpress
Project description:Embryonic stem cell (ESC) pluripotency is governed by a gene regulatory network centred on the transcription factors Oct4 and Nanog. ESCs fluctuate between states of high and low Nanog expression that direct efficient or inefficient self-renewal. To date, robust self-renewing ESC states have only been attained by chemical inhibition of signalling pathways or enforced transgene expression. Here we show that ESCs expressing a reduced range of Oct4 concentrations, typified by Oct4 heterozygous ESCs exhibit stable robust pluripotency. Despite this reduced Oct4 concentration range, this state is characterised by increased genome-wide binding of Oct4, particularly at pluripotency-associated enhancers, homogeneous expression of pluripotency transcription factors, enhanced self-renewal efficiency and delayed differentiation kinetics. In this state, ESCs exhibit increased wnt expression, enhanced LIF-sensitivity, non-responsiveness to FGF signalling and can clonally maintain pluripotency without BMP but remain dependent upon LIF. Robust pluripotency is destabilised either by alteration of the Oct4 level or by removal of LIF. Our findings suggest that robust pluripotency originates from cells with a reduced Oct4 protein concentration and that the wild-type Oct4 range enables effective differentiation.
2013-05-07 | E-MTAB-1617 | biostudies-arrayexpress