ESRG, a novel target of OCT4, maintains self-renewal and pluripotency of human pluripotent stem cells in collaboration with MCM2
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE190957 | GEO | 2023/03/02
REPOSITORIES: GEO
Similar Datasets
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: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 | 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 | GSE171627 | GEO
Project description:The role of ESRG in human pluripotency
| PRJNA659235 | ENA
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
Project description:Chickarmane2008 - Stem cell lineage - NANOG GATA-6 switch
In this work, a dynamical model of lineage
determination based upon a minimal circuit, as discussed in PMID: 17215298
, which contains the Oct4/Sox2/Nanog core as well its interaction
with a few other key genes is discussed.
This model is described in the article:
A computational model for understanding stem cell, trophectoderm and endoderm lineage determination.
Chickarmane V, Peterson C
PloS one. 2008, 3(10):e3478
Abstract:
BACKGROUND: Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4. METHODOLOGY/
PRINCIPAL FINDINGS: We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions; activation of Gata-6 by Oct4 and repression of Nanog by an Oct4-Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6.
CONCLUSIONS: The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state.
This model is hosted on BioModels Database
and identified
by: MODEL8389825246
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2008-12-05 | BIOMD0000000210 | BioModels
Project description:Chickarmane2008 - Stem cell lineage determination
In this work, a dynamical model of lineage
determination based upon a minimal circuit, as discussed in PMID: 17215298
, which contains the Oct4/Sox2/Nanog core as well its interaction
with a few other key genes is discussed.
This model is described in the article:
A computational model for understanding stem cell, trophectoderm and endoderm lineage determination.
Chickarmane V, Peterson C
PloS one. 2008, 3(10):e3478
Abstract:
BACKGROUND: Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties: self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4. METHODOLOGY/
PRINCIPAL FINDINGS: We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions; activation of Gata-6 by Oct4 and repression of Nanog by an Oct4-Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6.
CONCLUSIONS: The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state.
This model is hosted on BioModels Database
and identified
by: MODEL8390025091
.
To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource
for published quantitative kinetic models
.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to CC0 Public Domain
Dedication
for more information.
2008-12-05 | BIOMD0000000209 | BioModels