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Mapping the chemotherapy-induced RNA interactome in Glioblastoma [RNA-Seq]

ABSTRACT: Long non-coding RNAs (lncRNAs) are increasingly recognized as important players in transcription and epigenetic-driven cell diversification. So far, lncRNA function in more dynamic transcriptional reprogramming, i.e drug response, has been largely unexplored. Here, we investigated the regulatory circuits induced by chemotherapy in glioblastoma, the most aggressive and clinically refractory brain cancer. We performed a detailed characterization of the cellular and transcriptional response of glioblastoma stem-like cells to the alkylating agent temozolomide (TMZ). We found that in addition to mRNAs, TMZ affects the expression of a large number of non-coding RNAs (miRNAs, snoRNAs, lncRNAs). Our global transcriptome analysis provides a comprehensive characterization of regulatory circuits involving transcription factors, mRNAs, miRNAs and lncRNAs. To analyse the putative functions of these largely unknown RNA molecules, we developed a pipeline to integrate small and large RNA-seq data from multiple public databases and our own experiments. This led to the identification of the RNA interactome of glioblastoma and allowed us to define regulatory loops mediated by lncRNAs. We identified 22 key lncRNAs involved in transcriptional regulatory motifs, and three lncRNAs associated with patient prognosis, independent of other known response predictors. The investigation of TMZ-induced molecular networks in glioblastoma highlights novel coding and non-coding RNA-based predictors of glioblastoma chemoresistance, as well as potential targets to counteract such resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE98126 | GEO | 2019/04/24

REPOSITORIES: GEO

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Mapping the chemotherapy-induced RNA interactome in Glioblastoma [smallRNA-Seq]

Project description:Long non-coding RNAs (lncRNAs) are increasingly recognized as important players in transcription and epigenetic-driven cell diversification. So far, lncRNA function in more dynamic transcriptional reprogramming, i.e drug response, has been largely unexplored. Here, we investigated the regulatory circuits induced by chemotherapy in glioblastoma, the most aggressive and clinically refractory brain cancer. We performed a detailed characterization of the cellular and transcriptional response of glioblastoma stem-like cells to the alkylating agent temozolomide (TMZ). We found that in addition to mRNAs, TMZ affects the expression of a large number of non-coding RNAs (miRNAs, snoRNAs, lncRNAs). Our global transcriptome analysis provides a comprehensive characterization of regulatory circuits involving transcription factors, mRNAs, miRNAs and lncRNAs. To analyse the putative functions of these largely unknown RNA molecules, we developed a pipeline to integrate small and large RNA-seq data from multiple public databases and our own experiments. This led to the identification of the RNA interactome of glioblastoma and allowed us to define regulatory loops mediated by lncRNAs. We identified 22 key lncRNAs involved in transcriptional regulatory motifs, and three lncRNAs associated with patient prognosis, independent of other known response predictors. The investigation of TMZ-induced molecular networks in glioblastoma highlights novel coding and non-coding RNA-based predictors of glioblastoma chemoresistance, as well as potential targets to counteract such resistance.

2019-04-24 | GSE98127 | GEO

The different expression of long non-coding RNAs and messenger RNAs in temozolomide-resistant glioblastoma cells and parental glioblastoma cells

Project description:Temozolomide (TMZ) resistance may contribute to the treatment failure in patients with glioblastoma (GBM). Hence, understanding the underlying mechanisms and developing effective strategies against TMZ resistance are highly desired in the clinic. long non-coding RNAs (lncRNAs) have emerged as new regulatory molecules with diverse functions in biological processes and been deregulated in many pathologies, involved in the therapeutic resistance. It is urgent to elucidate the underlying lncRNA-based mechanisms of TMZ resistance in GBM patients.

2019-04-12 | GSE113510 | GEO

LncRNA and mRNA expression data from TMZ-resistant cell line

Project description:The discovery of long non-coding RNAs (lncRNAs) has improved the understanding of development and progression in various cancer sub-types. However, the role of lncRNAs in temozolomide (TMZ) resistance in glioblastoma (GBM) remains largely undefined. In this present study, the differential expression of lncRNAs were identified between U87 and U87TR (TMZ-resistant) cells and to find potential therapeutic targets of GBM for improving the survival of patients.

2022-03-30 | GSE199689 | GEO

LncRNA and mRNA expression data from TMZ-resistant cell line

Project description:Glioblastoma multiforme (GBM) is the most common and lethal malignant primary brain tumor. Temozolomide (TMZ) is a promising chemo-therapeutic agent to treat GBM. However, resistance to TMZ develops quickly with a high frequency. The mechanisms underlying GBM cells’ resistance to TMZ are not fully understood. Long non-coding RNAs (lncRNAs) are aberrantly expressed in many cancers and are highly involved in their pathogenesis including drug-resistence. In order to systematically study the role of lncRNAs in GBM cells' resistence to TMZ , we built gene expression profiles of TMZ-resistant cell line and TMZ-sensitive cell line using lncRNA and mRNA gene expression microarrays.

2020-07-03 | GSE100736 | GEO

Deshpande2019 - Random Forest model to predict long non-coding RNAs from coding RNAs in Zea Mays plant transcriptomic data

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2023-05-22 | BIOMD0000001067 | BioModels

HDAC6-LINC00461 pathway as a potential target for glioblastoma therapy

Project description:Background: Glioblastoma (GBM) is the most aggressive and lethal brain tumor. Although the histone deacetylase (HDAC)/Sp1 axis promotes growth and temozolomide (TMZ) resistance in glioblastoma, whether HDACs including HDAC6 are involved in modulating long non-coding RNAs (lncRNAs) to affect glioblastoma malignancy remains obscure. Methods: Integrative analysis of microarray and RNA-seq was performed to identify lncRNAs governed by HDAC6. Half-life measurement and RNA-protein pull-down assay combined with iTRAQ-based proteomic analysis were conducted to identify RNA modulators. The effect of LINC00461 on glioblastoma malignancy was evaluated using animal models and cell proliferation-related assays. Functional analysis of the LINC00461 downstream network was performed comprehensively using ingenuity pathway analysis and public databases. Results: We identified a lncRNA, LINC00461, which was substantially increased in TMZ-resistant glioblastoma cells. It was inversely correlated with the survival of mice bearing glioblastoma and was stabilized by interaction between HDAC6 and RNA-binding proteins (RBPs) such as CNOT6 and FUS. Targeting LINC00461 using MPT0B291, an HDAC6 inhibitor, decreased cell division-related proteins via the lncRNA-microRNA (miRNA)-mRNA network and caused cell cycle arrest, thereby suppressing proliferation in parental and TMZ-resistant glioblastoma cells and prolonging the survival of mice bearing glioblastoma. Conclusions: This study sheds light on the role of LINC00461 in glioblastoma malignancy and provides a novel therapeutic strategy for targeting the HDAC6/RBP/LINC00461 axis and its downstream effectors in patients with GBM.

2022-02-08 | GSE182220 | GEO

Transcriptome (RNA-Seq) of the stable overexpression of lncRNA XLOC013218 U251 cells

Project description:We present RNA-Seq data obtained from U251 control cells and U251 cells with stable overexpression of lncRNA XLOC13218 to identify differentially expressed genes. The discovery of long non-coding RNAs (lncRNAs) has improved the understanding of development and progression in various cancer sub-types. However, the role of lncRNAs in temozolomide (TMZ) resistance in glioblastoma (GBM) remains largely undefined. In this present study, the differential expression of lncRNAs were identified between U87 and U87TR (TMZ-resistant) cells. LncRNA XLOC013218 (XLOC) was drastically upregulated in TMZ-resistant cells and was associated with poor prognosis in glioma. Overexpression of XLOC markedly increased TMZ resistance, promoted proliferation, and inhibited apoptosis in vitro and in vivo. In addition, RNA-seq analysis and gain-of-function or loss-of-function studies revealed that PIK3R2 was the potential target of XLOC. Mechanistically, XLOC recruited Specificity Protein 1 (Sp1) transcription factor and promoted the binding of Sp1 to the promoters of PIK3R2, which elevated the expression of PIK3R2 in both mRNA and protein levels. Finally, PIK3R2-mediated activation of the PI3K/AKT signaling pathway promoted TMZ resistance and cell proliferation, but inhibited cell apoptosis. In conclusion, these data highlight the vital role of XLOC/Sp1/PIK3R2/PI3K/AKT axis in GBM TMZ resistance.

2022-04-05 | GSE200031 | GEO

Analyzing the interactions of mRNAs, miRNAs, lncRNAs and circRNAs to predict competing endogenous RNA networks in glioblastoma

Project description:Cross-talk between competitive endogenous RNAs (ceRNAs) may play a critical role in revealing potential mechanisms of tumor development and physiology. Glioblastoma is the most common type of malignant primary brain tumor, and the mechanisms of tumor genesis and development in glioblastoma are unclear. Here, to investigate the role of non-coding RNAs and the ceRNA network in glioblastoma, we performed paired-end RNA sequencing and microarray analyses to obtain the expression profiles of mRNAs, lncRNAs circRNAs and miRNAs. We identified that the expression of 501 lncRNAs, 1789 mRNAs, 2038 circRNAs and 143 miRNAs were often altered between glioblastoma and matched normal brain tissue. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on these differentially expressed mRNAs and miRNA-mediated target genes of lncRNAs and circRNAs. Furthermore, we used a multi-step computational framework and several bioinformatics methods to construct a ceRNA network combining mRNAs, miRNAs, lncRNAs and circRNA, based on co-expression analysis between the differentially expressed RNAs. We identified that plenty of lncRNAs, CircRNAs and their downstream target genes in the ceRNA network are related to glutamatergic synapse, suggesting that glutamate metabolism is involved in glioma biological functions. Our results will accelerate the understanding of tumorigenesis, cancer progression and even therapeutic targeting in glioblastoma. We hope to inspire researchers to study the role of non-coding RNAs in glioblastoma.

2016-08-30 | GSE86202 | GEO

MiRNA expression data from TMZ-resistant GBM cell line

Project description:Glioblastoma multiforme(GBM) is the most common and lethal malignant primary brain tumor. Temozolomide (TMZ) is a promising chemo-therapeutic agent to treat GBM. However, resistance to TMZ develops quickly with a high frequency. The mechanisms underlying GBM cells’ resistance to TMZ are not fully understood. Non-coding RNAs are aberrantly expressed in many cancers and are highly involved in their pathogenesis including drug-resistence. In order to systematically study the role of miRNAs in GBM cells' resistence to TMZ , we built gene expression profiles of TMZ-resistant cell line and TMZ-sensitive cell line using miRNA gene expression microarrays.

2020-07-04 | GSE100775 | GEO

Integrative classification of human coding and non-coding genes based on RNA metabolism profiles

Project description:The pervasive transcription of the human genome results in a heterogeneous mix of coding and long non-coding RNAs (lncRNAs). Only a small fraction of lncRNAs possess demonstrated regulatory functions, making it difficult to distinguish functional lncRNAs from non-functional transcriptional byproducts. This has resulted in numerous competing incoherent annotations of human lncRNA. To address these challenges, we quantitatively examined transcription, splicing, degradation, localization and translation for coding and non-coding human genes. Annotated lncRNAs had lower synthesis and higher degradation rates than mRNAs. We discovered mechanistic differences explaining the slower splicing of lncRNAs. We grouped genes into coherent classes by performing annotation-agnostic unsupervised classification of RNA metabolism profiles. These classes contained both mRNAs and lncRNAs to varying degrees; they exhibited distinct relationships between steps of RNA metabolism, evolutionary patterns, and sensitivity to cellular RNA regulatory pathways. Our classification provides a functionally coherent alternative to genomic context-driven annotations of lncRNAs.

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