OCT4 has an atheroprotective role in endothelial cells by preventing metabolic and phenotypic dysfunction
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ABSTRACT:
PROVIDER: PRJNA680613 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR13130455.fastq.gz | Fastqsanger.gz | |||
| SRR13130456.fastq.gz | Fastqsanger.gz | |||
| SRR13130457.fastq.gz | Fastqsanger.gz | |||
| SRR13130458.fastq.gz | Fastqsanger.gz | |||
| SRR13130459.fastq.gz | Fastqsanger.gz |
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Project description:Until recently, the pluripotency factor OCT4 was believed to be dispensable in adult somatic cells. However, our recent studies provided clear evidence that OCT4 has a critical atheroprotective role in smooth muscle cells (SMC). Here, we demonstrate that OCT4 controls endothelial cell (EC) phenotypic modulation in atherosclerosis. We establish a new atheroprotective function for OCT4, in that EC-specific Oct4 knockout resulted in increased lipid and LGALS3+ cell accumulation, and altered plaque characteristics consistent with decreased plaque stability. A combination of single-cell RNA sequencing and EC-lineage-tracing studies revealed increased EC activation, endothelial-to-mesenchymal transitions, plaque neovascularization, and mitochondrial dysfunction in the absence of OCT4. We show that ATP transporter, ABCG2, is a direct target of OCT4 in EC, and establish for the first time that the OCT4/ABCG2 axis maintains EC metabolic homeostasis by regulating intracellular heme accumulation and related reactive oxygen species production, which, in turn, contributes to atherogenesis. These results provide the first direct evidence that OCT4 has a protective metabolic function in EC, and identifies vascular OCT4 and its signaling axis as a potential target for novel therapeutics.
2022-04-02 | GSE162119 | GEO
Project description:AimsUntil recently, the pluripotency factor Octamer (ATGCAAAT)-binding transcriptional factor 4 (OCT4) was believed to be dispensable in adult somatic cells. However, our recent studies provided clear evidence that OCT4 has a critical atheroprotective role in smooth muscle cells. Here, we asked if OCT4 might play a functional role in regulating endothelial cell (EC) phenotypic modulations in atherosclerosis.Methods and resultsSpecifically, we show that EC-specific Oct4 knockout resulted in increased lipid, LGALS3+ cell accumulation, and altered plaque characteristics consistent with decreased plaque stability. A combination of single-cell RNA sequencing and EC-lineage-tracing studies revealed increased EC activation, endothelial-to-mesenchymal transitions, plaque neovascularization, and mitochondrial dysfunction in the absence of OCT4. Furthermore, we show that the adenosine triphosphate (ATP) transporter, ATP-binding cassette (ABC) transporter G2 (ABCG2), is a direct target of OCT4 in EC and establish for the first time that the OCT4/ABCG2 axis maintains EC metabolic homeostasis by regulating intracellular heme accumulation and related reactive oxygen species production, which, in turn, contributes to atherogenesis.ConclusionsThese results provide the first direct evidence that OCT4 has a protective metabolic function in EC and identifies vascular OCT4 and its signalling axis as a potential target for novel therapeutics.
| S-EPMC9890633 | biostudies-literature
Project description:The multiple claims about reactivation of the embryonic stem cell (ESC) pluripotency factor OCT4 in somatic cells are highly controversial due to the fact that there is no direct evidence that OCT4 has a functional role in cells other than ESCs. Herein we demonstrate that smooth muscle cell (SMC)-specific knockout of Oct4 within atherosclerotic mice resulted in increased lesion size and multiple changes consistent with decreased plaque stability. SMC-lineage tracing studies showed that lesions from SMC-specific conditional Oct4 KO mice had a reduced number of SMCs likely due to impaired SMC migration. RNA-seq analysis of lesion specimens showed that loss of Oct4 in SMCs was associated with marked activation of genes associated with inflammation and suppression of genes associated with cell migration, a number of which were shown to be activated in cultured SMCs by the combination of hypoxia and oxidized phospholipids in an OCT4-dependent manner. Activation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was HIF1α- and KLF4-dependent. Results provide the first genetic evidence that OCT4 plays a functional role in somatic cells and highlight the importance of further investigation of possible OCT4 functions in somatic cells.
2016-05-15 | GSE75044 | GEO
Project description:The multiple claims about reactivation of the embryonic stem cell (ESC) pluripotency factor OCT4 in somatic cells are highly controversial due to the fact that there is no direct evidence that OCT4 has a functional role in cells other than ESCs. Herein we demonstrate that smooth muscle cell (SMC)-specific knockout of Oct4 within atherosclerotic mice resulted in increased lesion size and multiple changes consistent with decreased plaque stability. SMC-lineage tracing studies showed that lesions from SMC-specific conditional Oct4 KO mice had a reduced number of SMCs likely due to impaired SMC migration. RNA-seq analysis of lesion specimens showed that loss of Oct4 in SMCs was associated with marked activation of genes associated with inflammation and suppression of genes associated with cell migration, a number of which were shown to be activated in cultured SMCs by the combination of hypoxia and oxidized phospholipids in an OCT4-dependent manner. Activation of Oct4 within SMCs was associated with hydroxymethylation of the Oct4 promoter and was HIF1α- and KLF4-dependent. Results provide the first genetic evidence that OCT4 plays a functional role in somatic cells and highlight the importance of further investigation of possible OCT4 functions in somatic cells. In vivo: mRNA profiles of 18 week fed Western diet wild type (WT) and Oct4-/- mice were generated by deep sequencing, four animals per group, using Illumina HiSeq 2000. In vitro: a smooth muscle cell wild type (WT) and Oct4-/- (KO) primary aortic cell line was generated and used. mRNA profiles were generated by deep sequencing, in triplicates, using Illumina HiSeq 2000, for the following groups: WT-normoxia-vehicle; WT-normoxia-POVPC; KO-normoxia-vehicle; KO-normoxia-POVP; WT-hypoxia-vehicle; WT-hypoxia-POVPC; KO-hypoxia-vehicle; and KO-hypoxia-POVPC.
2016-05-15 | E-GEOD-75044 | biostudies-arrayexpress
Project description:We examined the potential utility of L-carnitine for alleviating metabolic dysfunction-associated steatohepatitis (MASH) and preventing the development of hepatocellular carcinoma. Short-term L-carnitine administration ameliorated MASH through its anti-inflammatory effects.
2024-04-24 | GSE261938 | GEO
Project description:Atherosclerosis is a focal disease that preferentially develop in the regions of atheroprone disturbed flow, but less in regions of atheroprotective laminar flow. The mechanisms by which atheroprotective laminar flow prevents atherosclerosis at the epigenetic level remain largely unknown. In this study, we observed that laminar flow decreased histone methyltransferase EZH2, which imposes a repressive epigenetic mark of histone 3 lysine 27 trimethylation (H3K27me3) onto target gene promoters, leading to transcriptional silencing. To evaluate the effect of atheroprotective flow on EZH2 and H3K27me3 dependent genome-wide transcriptional profile, we performed RNA-sequencing study on laminar flow and EZH2 siRNA treated human endothelial cells. Venn diagram was used to compare the common regulated genes by both laminar flow and EZH2 depletion. We found atheroprotective flow and EZH2 depletion altere endothelial gene landscape, which include upregulating atheroprotective genes while downregulating pro-atherosclerotic genes.
2017-09-30 | GSE87534 | GEO
Project description:ChIP Seq of Oct4, Nanog, H3K27me3 in Oct4+/+ and Oct4 +/- mES cells
| PRJEB1833 | ENA
Project description:E7 modulates Oct4 re-expression in cervical cancer
2023-04-06 | MSV000091651 | MassIVE
Project description:In two widely-cited OCT4-protein interactome papers, Ding et al. (Ding et al., 2012) used murine ESC nuclear extract to identify OCT4 interactome in nucleus and Pardo et al. (Pardo et al., 2010) used whole cell lysate to identify OCT4 interactome in murine ESCs. In both papers, Benzonase, a genetically engineered endonuclease was employed to fragment genome DNA which significantly improved the enrichment efficiency of nuclear TFs. Since our focus was on cytosolic pool of OCT4, we used mild conditions for cell lysis and modified the Pardo’s method by omitting the addition of any nucleases to the lysis buffer. Such conditions not only retained the protein/RNA interactions, but also enabled precipitation of the nuclear TFs with genome DNA, and hence a relative enrichment of the cytosolic proteins and other soluble nuclear proteins (such as splicing factors) in the supernatant, and therefore allowed us to minimize the interference of the TF roles of OCT4 and to focus more on its novel RBP roles.
2025-05-06 | PXD033840 | Pride
Project description:Oct4 is a master regulator of pluripotency. Potential Oct4 interactors have been cataloged extensively but the manner and significance of these interactions are incompletely defined. Like other POU domain proteins, Oct4 is capable of binding to DNA in multiple configurations, however the relationship between these configurations and cofactor recruitment (and hence transcription output) are unknown. Here, we show that Oct4 interacts with common and unique proteins when bound to DNA in different configurations. One of these proteins is Jade1, a component of the HBO histone acetyltransferase complex. Jade1 preferentially associates with Oct4 when bound to More palindromic Octamer-Related Element (MORE) DNA sequences that bind Oct4 dimers and are associated with strong gene expression. We show that the Oct4 N-terminus is critical for this interaction. ChIP-seq using HBO1, the enzymatic component of the complex, identifies a preference for binding adjacent to Oct4 at MORE sites. Using purified recombinant proteins and nucleosome complexes, we show that the HBO1 complex acetylates histone H3K9 within nucleosomes more efficiently when Oct4 is co-bound to a MORE site. Histone acetylation is further increased when Oct4 is mutated to favor dimeric MORE binding. Cryo-electron microscopy reveals that Oct4 bound to a MORE near the nucleosome entry/exit site partially unwinds DNA from nucleosome core particles, and identifies additional mass associated with the HBO1 complex. These results identify a novel mechanism of transcriptional regulation by Oct4.
2024-10-18 | MSV000096131 | MassIVE