Monitoring rapid degradation of NANOG reveals UTP15 maintains pluripotency by regulating nascent transcripts
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE276879 | GEO | 2025/10/23
REPOSITORIES: GEO
Similar Datasets
Project description:Master transcription factors (MTFs) are key regulators in cell fate determination. However, an approach to profile MTF’s direct transcriptional targets together with their associated RNA-binding proteins (RBPs), is still lacking. Here, we applied 5-ethynyluridine RNA metabolic labelling and click chemistry to map the dynamics of the transcriptional targets and the RBPs interacting with the newly transcribed RNAs upon acute NANOG degradation in mouse embryonic stem cells (mESCs). We identified UTP15, a classic rRNA-biogenesis regulator, acts as a key activator of pluripotency-associated gene transcription independently of rRNA biogenesis. Importantly, NANOG-regulated transcription enhances UTP15 binding to transcription start sites (TSSs), associated with increased Pol II binding and more active transcription. Moreover, UTP15 promotes the assembly of Pol II biomolecular condensates, thereby potentially driving pluripotency gene transcription. Collectively, our study uncovers a NANOG-nascent transcript-UTP15 regulatory axis to activate pluripotency gene transcription, providing a distinct approach for studying MTF’s function during cell fate determination.
2025-10-23 | GSE276878 | GEO
Project description:Master transcription factors (MTFs) are key regulators in cell fate determination. However, an approach to profile MTF’s direct transcriptional targets together with their associated RNA-binding proteins (RBPs), is still lacking. Here, we applied 5-ethynyluridine RNA metabolic labelling and click chemistry to map the dynamics of the transcriptional targets and the RBPs interacting with the newly transcribed RNAs upon acute NANOG degradation in mouse embryonic stem cells (mESCs). We identified UTP15, a classic rRNA-biogenesis regulator, acts as a key activator of pluripotency-associated gene transcription independently of rRNA biogenesis. Importantly, NANOG-regulated transcription enhances UTP15 binding to transcription start sites (TSSs), associated with increased Pol II binding and more active transcription. Moreover, UTP15 promotes the assembly of Pol II biomolecular condensates, thereby potentially driving pluripotency gene transcription. Collectively, our study uncovers a NANOG-nascent transcript-UTP15 regulatory axis to activate pluripotency gene transcription, providing a distinct approach for studying MTF’s function during cell fate determination.
2025-10-23 | GSE276877 | GEO
Project description:Master transcription factor (mTF) has been recognized as topmost regulatory hierarchy in cell fate determination. However, the direct transcriptional targets of mTFs, and how the interplay between these transcriptional targets and their associated RNA-binding proteins (RBPs) orchestrate the realisation of mTF functions, remain largely unknown. Here, we analysed transcriptional targets and their associated RBPs during acute depletion of NANOG in mouse embryonic stem cells (mESCs) using 5-ethynyluridine (EU) RNA metabolic labelling and click chemistry. We found that UTP15 is a sensor of NANOG transcriptional targets that maintains self-renewal of mESCs. Mechanistically, UTP15 is recruited to chromatin by NANOG transcriptional targets to maintain transcription of pluripotency-related genes. In conclusion, we provide a new paradigm to study the function of mTF and establish the mTF-nascent RNA-RBP axis that regulates cell fate decisions.
2025-10-28 | PXD043911 | Pride
Project description:RNA-binding proteins (RBPs) play integral roles in gene regulation, yet only a small fraction of RBPs has been studied in the context of stem cells. We here apply RNA interference screen for RBPs in mouse embryonic stem cells (ESCs) and identify 16 RBPs involved in pluripotency maintenance. Interestingly, six identified RBPs including Krr1 and Ddx47 are part of a complex called Small Subunit Processome (SSUP) that mediates 18S rRNA biogenesis. The SSUP components are preferentially expressed in stem cells and enhance global translational rate, which is critical to sustain the protein levels of labile pluripotency factors such as Nanog and Esrrb. Furthermore, the SSUP proteins are required for efficient reprogramming of induced pluripotent stem cells. Our study uncovers the role of SSUP and the importance of translational control in stem cell fate decision. R1 cells were transfected with 3 different control siRNAs and 3 different siRNAs targeting Krr1 for 48 hrs. Transcriptome profiles were generated by deep sequencing using illumina HiSeq 2000.
2015-09-24 | E-GEOD-73369 | biostudies-arrayexpress
Project description:RNA-binding proteins (RBPs) play integral roles in gene regulation, yet only a small fraction of RBPs has been studied in the context of stem cells. We here apply RNA interference screen for RBPs in mouse embryonic stem cells (ESCs) and identify 16 RBPs involved in pluripotency maintenance. Interestingly, six identified RBPs including Krr1 and Ddx47 are part of a complex called Small Subunit Processome (SSUP) that mediates 18S rRNA biogenesis. The SSUP components are preferentially expressed in stem cells and enhance global translational rate, which is critical to sustain the protein levels of labile pluripotency factors such as Nanog and Esrrb. Furthermore, the SSUP proteins are required for efficient reprogramming of induced pluripotent stem cells. Our study uncovers the role of SSUP and the importance of translational control in stem cell fate decision.
2015-09-24 | GSE73369 | GEO
Project description:Mutations of NBS1 gene result in Nijmegen breakage syndrome (NBS), and the gene encodes NBS1 that forms a complex with MRE11 and RAD50 and participates in DNA damage repair. However, the molecular mechanism by which the mutations of NBS1 cause clinical phenotypes of NBS, such as craniofacial dysmorphism, is still unclear. Here, we show that NBS1 localizes at the rDNA loci in the nucleoli and interacts with ribosome RNA (rRNA) transcription machinery including RNA polymerase I (Pol I) and TCOF1. Loss of NBS1 impairs Pol I-dependent transcription of pre-rRNA and induces nucleolar stress. In particular, lacking Nbs1 in mouse neural crest cells not only leads to the reduction of ribosome biogenesis but also craniofacial abnormalities during prenatal development. Moreover, the C-terminus of NBS1 is associated with pre-rRNA and a number of pre-rRNA processing factors, which may also facilitate pre-rRNA maturation. Taken together, our study reveals the functions of NBS1 in rRNA biogenesis.
2025-02-24 | PXD061157 |
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.
2024-09-02 | BIOMD0000000209 | BioModels
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.
2024-09-02 | BIOMD0000000210 | BioModels
Project description:Mutations of NBS1 gene result in Nijmegen breakage syndrome (NBS), and the gene encodes NBS1 that forms a complex with MRE11 and RAD50 and participates in DNA damage repair. However, the molecular mechanism by which the mutations of NBS1 cause clinical phenotypes of NBS, such as craniofacial dysmorphism, is still unclear. Here, we show that NBS1 localizes at the rDNA loci in the nucleoli and interacts with ribosome RNA (rRNA) transcription machinery including RNA polymerase I (Pol I) and TCOF1. Loss of NBS1 impairs Pol I-dependent transcription of pre-rRNA and induces nucleolar stress. In particular, lacking Nbs1 in mouse neural crest cells not only leads to the reduction of ribosome biogenesis but also craniofacial abnormalities during prenatal development. Moreover, the C-terminus of NBS1 is associated with pre-rRNA and a number of pre-rRNA processing factors, which may also facilitate pre-rRNA maturation. Taken together, our study reveals the functions of NBS1 in rRNA biogenesis.
2025-09-15 | PXD056042 | Pride
Project description:Ribosome biogenesis is a highly regulated multistep process that controls cell growth and proliferation. The first and key regulatory step of ribosome biogenesis is represented by the transcription of ribosomal RNA (rRNA) genes by RNA polymerase (pol) I in the nucleolus. Activity of RNA pol I is tightly regulated by interactions with many auxiliary factors that mediate promoter recognition and contribute to transcription initiation, elongation and termination. In this study we were able to identify by mass spectrometry some of the known components of the RNA pol I transcribing machinery, and at the same time we identify some novel interactors.
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