Oct4 activates a Suv39h1-repressive antisense lncRNA to couple histone H3 lysine methylation to pluripotency
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA763352 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15902163.fastq.gz | Fastqsanger.gz | |||
| SRR15902164.fastq.gz | Fastqsanger.gz | |||
| SRR15902165.fastq.gz | Fastqsanger.gz | |||
| SRR15902166.fastq.gz | Fastqsanger.gz | |||
| SRR15902167.fastq.gz | Fastqsanger.gz |
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Project description:Histone H3 Lysine 9 (H3K9) methylation, a characteristic mark of heterochromatin, is progressively implemented during development to contribute to cell fate restriction as differentiation proceeds. Accordingly, in undifferentiated and pluripotent mouse Embryonic Stem (ES) cells the global levels of H3K9 methylation are rather low and increase only upon differentiation. How global H3K9 methylation levels are coupled with the loss of pluripotency remains largely unknown. Here, we identify SUV39H1, a major H3K9 di- and tri-methylase, as an indirect target of the pluripotency network of Transcription Factors (TFs). We find that pluripotency TFs, principally OCT4, activate the expression of Suv39h1as, an antisense long non-coding RNA to Suv39h1. In turn, Suv39h1as downregulates Suv39h1 transcription in cis via a mechanism involving the modulation of the chromatin status of the locus. The targeted deletion of the Suv39h1as promoter region triggers increased SUV39H1 expression and H3K9me2 and H3K9me3 levels, affecting all heterochromatic regions, particularly peri-centromeric major satellites and retrotransposons. This increase in heterochromatinization efficiency leads to accelerated and more efficient commitment into differentiation. We report, therefore, a simple genetic circuitry coupling the genetic control of pluripotency with the global efficiency of H3K9 methylation associated with a major cell fate restriction, the irreversible loss of pluripotency.
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Project description:We report RNA-seq expression data of different cell lines of mouse embryonic stem cells in self-renewal conditions and upon the inactivation of Oct4 or Esrrb. ChIP-seq of H3K9me3 and ATAC-seq data of wild-type and Suv39h1as deleted cells are also provided.
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Project description:HeLa cells were transiently transfected with siRNA against SUV39H1, a histone H3K9 methyltransferase. Several genes were significantly up- or down-regulated. HeLa cells were transiently transfected with siRNA against SUV39H1 or negative control siRNA. Then total RNA was extracted.
2015-08-01 | E-GEOD-59243 | biostudies-arrayexpress
Project description:Oncogene-induced senescence (OIS), a terminal cell cycle block countering (pre)neoplastic lesions, is characterised on the molecular level by trimethylated histone H3 lysine 9 (h3K9me3), a transcriptionally repressive chromatin mark linked to silencing of S-phase-promoting genes. Whether H3K9-governed chromatin remodelling influences anticancer treatment-induced senescence (TIS) and whether functional control of this mark impacts on treatment outcome is not known. We used global gene expression profiling by microarrays to gain insight into the molecular responses of Emu-myc; Suv39h1-/- B-cell lymphoma cells to senescence-inducing anticancer agent Adriamycin (ADR). Primary lymphoma cells isolated from lymph nodes of Emu-Myc; Suv39h1-/- mice were used. In this model, the c-Myc oncogene is constitutively expressed in the cells of the B-cell lineage, leading to spontaneous development of aggressive B-cell lymphomas. Adriamycin (ADR), a cytostatic drug used as a standard part of several lymphoma treatment regimens, is known to massively induce TIS in Suv39h1-proficient lymphomas, protected from apoptosis by Bcl-2 over expression (Myc;Bcl2). In order to discern the impact of Suv39h1 to TIS induction under these conditions, we analysed here transcriptional profiles of matched pairs of Emu-myc;Suv39h1-/-;Bcl2 lymphomas, untreated or treated for 5 days with ADR.
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Project description:Glioblastoma (GBM) is the deadliest brain cancer, driven in part by GBM stem cells (GSCs) that contribute to therapeutic resistance and tumor recurrence. Effective targeting and elimination of GSCs hold promise for preventing GBM recurrence and achieving potential cures. In this study, we explored the role of the epigenetic regulator SUV39H1 in GSC maintenance and GBM progression. We observed that SUV39H1 is upregulated in GBM samples compared to normal brain tissues. Single-cell RNA-seq data indicated that SUV39H1 is preferentially expressed in GSCs relative to non-stem GBM cells, possibly due to super-enhancer-mediated transcriptional activation. Knockdown of SUV39H1 in patient-derived GSCs impaired their proliferation and stemness. RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. Integrated ATAC-seq (assay for transposase-accessible chromatin followed by sequencing) and RNA-seq analyses demonstrated that targeting SUV39H1 altered chromatin accessibility in key genes associated with these pathways. Treatment with chaetocin, a SUV39H1 inhibitor, mimicked the effects of SUV39H1 knockdown in GSCs and sensitized them to the GBM chemotherapy drug temozolomide (TMZ). In vivo studies using an intracranial patient-derived xenograft model showed that targeting SUV39H1 inhibited GSC-driven tumor formation in mice. Our findings identify SUV39H1 as a critical regulator of GSC maintenance and suggest that targeting SUV39H1 could disrupt GSCs and enhance the efficacy of existing chemotherapy, offering a promising strategy for improving GBM treatment outcomes.
2024-11-06 | GSE273012 | GEO
Project description:Glioblastoma (GBM) is the deadliest brain cancer, driven in part by GBM stem cells (GSCs) that contribute to therapeutic resistance and tumor recurrence. Effective targeting and elimination of GSCs hold promise for preventing GBM recurrence and achieving potential cures. In this study, we explored the role of the epigenetic regulator SUV39H1 in GSC maintenance and GBM progression. We observed that SUV39H1 is upregulated in GBM samples compared to normal brain tissues. Single-cell RNA-seq data indicated that SUV39H1 is preferentially expressed in GSCs relative to non-stem GBM cells, possibly due to super-enhancer-mediated transcriptional activation. Knockdown of SUV39H1 in patient-derived GSCs impaired their proliferation and stemness. RNA-seq analysis revealed that SUV39H1 regulates G2/M cell cycle progression, stem cell maintenance, and cell death pathways in GSCs. Integrated ATAC-seq (assay for transposase-accessible chromatin followed by sequencing) and RNA-seq analyses demonstrated that targeting SUV39H1 altered chromatin accessibility in key genes associated with these pathways. Treatment with chaetocin, a SUV39H1 inhibitor, mimicked the effects of SUV39H1 knockdown in GSCs and sensitized them to the GBM chemotherapy drug temozolomide (TMZ). In vivo studies using an intracranial patient-derived xenograft model showed that targeting SUV39H1 inhibited GSC-driven tumor formation in mice. Our findings identify SUV39H1 as a critical regulator of GSC maintenance and suggest that targeting SUV39H1 could disrupt GSCs and enhance the efficacy of existing chemotherapy, offering a promising strategy for improving GBM treatment outcomes.
2024-11-06 | GSE273013 | GEO
Project description:Pseudogene-derived, long non-coding RNAs (lncRNAs) act as epigenetic regulators of gene expression. Here we present a panel of new mouse Oct4 pseudogenes and demonstrate that the X-linked Oct4 pseudogene Oct4P4 critically impacts mouse embryonic stem cells (mESCs) self-renewal. Sense Oct4P4 transcription produces a spliced, nuclear-restricted lncRNA that is efficiently upregulated during mESC differentiation. Oct4P4 lncRNA forms a complex with the SUV39H1 HMTase to direct the imposition of H3K9me3 and HP1α to the promoter of the ancestral Oct4 gene, located on chromosome 17, leading to gene silencing and reduced mESC self-renewal. Targeting Oct4P4 expression in primary mouse embryonic fibroblasts causes the re-acquisition of self-renewing features of mESC. We demonstrate that Oct4P4 lncRNA plays an important role in inducing and maintaining silencing of the ancestral Oct4 gene in differentiating mESCs. Our data introduces a sense pseudogene-lncRNA-based mechanism of epigenetic gene regulation that controls the cross-talk between pseudogenes and their ancestral genes.
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Project description:This SuperSeries is composed of the following subset Series: GSE39746: Argonaute proteins couple chromatin silencing to alternative splicing (exon array) GSE39748: Argonaute proteins couple chromatin silencing to alternative splicing (RNA IP-Seq) Refer to individual Series
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Project description:ChIP Seq of Oct4, Nanog, H3K27me3 in Oct4+/+ and Oct4 +/- mES cells
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Project description:Epigenetic regulation is a pivotal factor during neuroblastoma (NB) pathogenesis and investigations into cancer epigenetics are actively underway to identify novel therapeutic strategies for NB patients. SUV39H1, a member of the H3K9 methyltransferase family, contributing to tumorigenesis across multiple malignancies. However, its specific role in NB remains unexplored. In this study, we conducted a high-throughput screen utilizing a compound library containing 288 epigenetic drugs, leading to the identification of chaetocin as the most potent NB inhibitor by targeting SUV39H1. Genetic manipulation and therapeutic inhibition of SUV39H1 significantly impacted proliferation, migration, cell cycle phases, and apoptosis in NB cells. Concurrently, chaetocin demonstrated robust anti-tumor efficacy in vivo with tolerable toxicity. RNA-seq unveiled that SUV39H1 knockdown and inhibition down-regulated cell cycle pathways, impacting vital genes such as AURKA. Besides, MCPIP1 emerged as a novel tumor suppressor following SUV39H1 inhibition, which decreased AURKA expression in NB. In detail, SUV39H1 mediated the enrichment of H3K9me3 at the promoter region of MCPIP1, repressing the MCPIP1-mediated degradation of AURKA and facilitating the subsequent accumulation of AURKA, which revealed the oncogenic role of SUV39H1 via the SUV39H1-MCPIP1-AURKA signaling axis in NB. Therapeutic inhibition of SUV39H1 using chaetocin emerges as an effective and safe strategy for NB patients.
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