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The THO complex regulates pluripotency gene mRNA export to control embryonic stem cell self-renewal and somatic cell reprogramming (microarray)

ABSTRACT: Embryonic stem cell (ESC) self-renewal and differentiation are governed by a broad-ranging regulatory network. Although the transcriptional regulatory mechanisms involved have been investigated extensively, post-transcriptional regulation is still poorly understood. Here we describe a critical role of the THO complex in ESC self-renewal and differentiation. We show that THO preferentially interacts with pluripotency gene transcripts through Thoc5, and is required for self-renewal at least in part by regulating their export and expression. During differentiation, THO loses its interaction with those transcripts due to reduced Thoc5 expression, leading to decreased expression of pluripotency proteins that facilitates exit from self-renewal. THO is also important for the establishment of pluripotency, as its depletion inhibits somatic cell reprogramming and blastocyst development. Together, our data indicate that THO regulates pluripotency gene mRNA export to control ESC self-renewal and differentiation, and therefore uncover a role for this aspect of post-transcriptional regulation in stem cell fate specification.

ORGANISM(S): Mus musculus

PROVIDER: GSE51496 | GEO | 2013/11/30

SECONDARY ACCESSION(S): PRJNA223316

REPOSITORIES: GEO

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The THO complex regulates pluripotency gene mRNA export to control embryonic stem cell self-renewal and somatic cell reprogramming (microarray)

Project description:Embryonic stem cell (ESC) self-renewal and differentiation are governed by a broad-ranging regulatory network. Although the transcriptional regulatory mechanisms involved have been investigated extensively, post-transcriptional regulation is still poorly understood. Here we describe a critical role of the THO complex in ESC self-renewal and differentiation. We show that THO preferentially interacts with pluripotency gene transcripts through Thoc5, and is required for self-renewal at least in part by regulating their export and expression. During differentiation, THO loses its interaction with those transcripts due to reduced Thoc5 expression, leading to decreased expression of pluripotency proteins that facilitates exit from self-renewal. THO is also important for the establishment of pluripotency, as its depletion inhibits somatic cell reprogramming and blastocyst development. Together, our data indicate that THO regulates pluripotency gene mRNA export to control ESC self-renewal and differentiation, and therefore uncover a role for this aspect of post-transcriptional regulation in stem cell fate specification. mouse J1 cells were transfected with non-targeting (NT), Thoc2, and Thoc5 siRNAs. Total RNA was isolated 96 hours after transfection.

2013-11-30 | E-GEOD-51496 | biostudies-arrayexpress

The THO complex regulates pluripotency gene mRNA export to control embryonic stem cell self-renewal and somatic cell reprogramming (RNA-IP)

Project description:Embryonic stem cell (ESC) self-renewal and differentiation is governed by a comprehensive regulatory network. Although the transcriptional regulation has been extensively investigated, post-transcriptional mechanisms controlling the ESC state are poorly understood. Here we describe a critical role of the THO complex in ESC self-renewal and differentiation. We show that THO preferentially interacts with pluripotency gene transcripts through Thoc5, and is required for self-renewal by regulating their export and expression. During differentiation, THO loses its interaction with those transcripts due to reduced Thoc5 expression, which leads to decreased expression of pluripotency proteins and facilitates differentiation. Finally, THO is also important for the establishment of pluripotency, as its depletion inhibits somatic cell reprogramming and blastocyst development. Together, our data indicates that THO regulates pluripotency gene mRNA export to control ESC self-renewal and differentiation, and uncovers a novel mechanism of post-transcriptional regulation in stem cell fate specification. RNA IP was conducted by use of antibody against Thoc2, the precipitated RNA was used to generate library using illumina Kit, and subsequently sequenced by miSeq

2013-11-30 | E-GEOD-48436 | biostudies-arrayexpress

The THO complex regulates pluripotency gene mRNA export to control embryonic stem cell self-renewal and somatic cell reprogramming (RNA-IP)

2013-11-30 | GSE48436 | GEO

THOC5 complexes with other proteins (DDX5, DDX17 and CDK12) essential in primitive cell survival to regulate R loop structures and RNA elongation rate.

Project description:THOC5, a member of the THO complex, is essential for the 3´processing of some inducible genes, the export of a subset of genes and stem cell self-renewal. Utilising nanopore mRNA-sequencing we show that when THOC5 is depleted 50% of mRNAs undergo altered 3´end cleavage. Further, THOC5 depletion leads to increased RNA Polymerase II (Pol II) presence on the gene body and close to the 3’end. Moreover, THOC5 is recruited close to high density Pol II sites except those at the promotor regions suggesting that THOC5 is involved in transcriptional elongation. Indeed, THOC5 independent genes in cells expressing fast Pol II became THOC5 dependent in cells expressing slow Pol II. In cells expressing slow Pol II chromatin associated THOC5 interacts with CDK12 (a protein that modulates mRNA elongation rates), RNA helicases DDX5, DDX17, and THOC6. Importantly these interactions were not observed in cells expressing fast Pol II. The CDK12/THOC5 interaction promotes CDK12 recruitment to R-loops in a THOC6-dependent manner. These data demonstrate that THOC5/THOC6 play a part in transcription elongation. Given the role of THOC5 in primitive cell survival its phosphorylation by agonists, oxidative stress and oncogenes the pathway we identified has relevance in the physiology and pathology of stem cells

2022-12-12 | PXD035092 | Pride

The THO Complex-Dependent Posttranscriptional Control Contributes to Vascular Smooth Muscle Cell Fate Decision

Project description:We applied RNA-Seq to analyze the effects of silencing of Thoc2 or Thoc5, two components of the THO complex, in cultured VSMC. The result revealed that Thoc5 silencing closely resembled the gene expression changes induced upon PDGF-BB/PDGF-DD treatments in cultured VSMCs. Mechanistically, our RIP-Seq data revealed both Thoc2 and Thoc5 preferentially interacted with VSMC marker gene mRNAs and mediated their expression. Interestingly, mRNAs that lost Thoc2 or Thoc5 binding during VSMC dedifferentiation were enriched for genes important for VSMC identity. In addition, silencing of Thoc2 or Thoc5 led to dedifferentiation of VSMCs in vitro, characterized by decreased VSMC marker gene expression and increased migration and proliferation. Furthermore, we performed immuno-histochemical staining against Thoc2 and Thoc5, and found a dramatic reduction in their expression in human arteries undergoing carotid endarterectomy (CEA) compared to normal internal mammary arteries (IMA). Notably, Thoc5 overexpression in injured rat carotid arteries significantly repressed loss of VSMC marker gene expression and neointima formation. Together, our data introduce dynamic binding of THO to VSMC marker gene mRNAs as a novel mechanism contributing to VSMC fate decisions, and imply Thoc5 as a potential intervention node for vascular diseases.

2018-12-06 | GSE116850 | GEO

The THO complex regulates pluripotency gene mRNA export to control embryonic stem cell self-renewal and somatic cell reprogramming

Project description:The THO complex regulates pluripotency gene mRNA export to control embryonic stem cell self-renewal and somatic cell reprogramming

| PRJNA223385 | ENA

A member of transcription/export complex (TREX), THOC5 controls elongation rate by recruiting CDK12.

Project description:THOC5, a member of the THO complex that is a subcomplex of Transcription/export complex (TREX) 1, is essential for 3´processing of slow kinetics IEGs, and for export of only a subset of genes. Applying nanopore mRNA-sequence technology, we show here that upon depletion of THOC5, 50% of mRNAs showed alteration of 3´end cleavage sites. Moreover, polymerase-II (Pol II)-CHIP-sequencing data reveals that upon depletion of THOC5 Pol II density was increased at gene body and 3´UTR. THOC5 is recruited near to Pol II high density sites except promotor regions, suggesting that THOC5 is involved in transcription elongation. Indeed, 385 THOC5 independent genes in fast Pol II cells became THOC5 dependent in slow Pol II cells. Chromatin associated THOC5 in slow Pol II cells interacts with CDK12, RNA helicases DDX5 and DDX, and THOC6, but not with other members of THO complex. Notably, THOC5 did not form this complex in fast poly II cells. CDK12 was recruited to R-loop (DNA:RNA hybrid) in THOC5/THOC6 dependent manner. Here, THOC6, but not THOC5 directly interacts with R-loop then, recruited DDX5 resolves R-loop and then CDK12 enhances further transcription elongation. These data show for the first time the novel function of THOC5/THOC6 complex during transcription elongation.

2022-12-31 | GSE166115 | GEO

THOC5 complexes with DDX5, DDX17 and CDK12 to regulate R loop structures and transcription elongation rate

Project description:THOC5, a member of the THO complex, is essential for the 3´processing of some inducible genes, the export of a subset of genes and stem cell self-renewal. Utilising nanopore mRNA-sequencing we show that when THOC5 is depleted 50-60% of mRNAs undergo altered 3´end cleavage. Further, THOC5 depletion leads to increased RNA Polymerase II (Pol II) presence at the start site, on the gene body and close to the 3’end. Moreover, THOC5 is recruited close to high density Pol II sites suggesting that THOC5 is involved in transcriptional elongation. Indeed, DRB/TTchem-seq that measures elongation rates in vivo revealed an accumulation of released Pol II near to TSS and a decrease of elongation rates in THOC5 depleted cells. Furthermore, THOC5 is more recruited to its target genes in cells expressing slow Pol II than those expressing fast Pol II. In cells expressing slow Pol II chromatin associated THOC5 interacts with CDK12 (a protein that modulates mRNA elongation rates), RNA helicases DDX5, DDX17, and THOC6. Importantly these interactions were not observed in cells expressing fast Pol II. 3’ cleavage of 50% of THOC5 target genes is also regulated by CDK12 and THOC6. The CDK12/THOC5 interaction promotes CDK12 recruitment to R-loops in a THOC6-dependent manner. These data demonstrate that THOC5/THOC6 play a part in transcription elongation. Given the role of THOC5 in primitive cell survival its phosphorylation by agonists, oxidative stress and oncogenes the pathway we identified has relevance in the physiology and pathology of stem cells.

2022-12-16 | GSE173374 | GEO

Expression data from Saccharomyces cerevisiae strains deleted for different subunits of the THO/TREX complex

Project description:THO/TREX is a conserved nuclear complex that functions in mRNP biogenesis at the interface of transcription-RNA export with a key role in preventing transcription-associated genome instability. We used microarrays to analyze the impact of different THO/TREX mutations on gene expression and found that THO-Sub2 deletions have a high functional impact on highly expressed, long and G+C-rich genes regardless of gene function.

2011-06-29 | GSE24802 | GEO

Musashi2 is required for the self-renewal and pluripotency of embryonic stem cells

Project description:Recent studies have shown that the RNA binding protein Musashi 2 (Msi2) plays prominent roles during development and leukemia. Additionally, in embryonic stem cells (ESC) undergoing the early stages of differentiation, Msi2 has been shown to associate with Sox2, which is required for the self-renewal of ESC. These findings led us to examine the effects of Msi2 on the behavior of ESC. Using an shRNA sequence that targets Msi2 and a scrambled shRNA sequence, we determined that knockdown of Msi2 disrupts the self-renewal of ESC and promotes their differentiation. Collectively, our findings argue that Msi2 is required to support the self-renewal and pluripotency of ESC. We used microarrays to better understand global changes in ESC gene expression following the knockdown of the RNA-binding protein Msi2 as compared to control ESC expressing a scrambled shRNA.

2012-08-25 | GSE33882 | GEO

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