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Gene expression in GSCs with shALKBH5

ABSTRACT: Knocking down ALKBH5 in Glioma Stem Cells resulted in an altered gene expression profile N6-methyl-adenosine (m6A) is the most prevalent internal chemical modification of mRNAs in eukaryotes. In mammals, m6A installed by m6A methyltransferases METTL3 and METTL14 is erased by two members of the AlkB family of nonheme Fe(II)/a-ketoglutarate (a-KG)-dependent dioxygenases, fat-mass and obesity associated protein (FTO) or ALKBH5. ALKBH5 affects nuclear RNA export and metabolism, gene expression and mouse fertility. To date, little is known about the biological significance of m6A in human cancer. We found that ALKBH5 is highly expressed in human glioblastoma stem cells which are resistant to conventional therapy and give rise to glioblastoma recurrence by sustaining long-term tumor growth. Global manipulation of the m6A modification by depleting ALKBH5 resulted in altered gene expression including subsets of genes enriched in "Cell Cycle", "DNA Replication, Recombination, and Repair" and "Cellular Assembly and Organization". Knockdown of ALKBH5 expression in human glioblastoma stem cells significantly reduced their self-renewal ability as a result of inhibition of cell cycle progression. This study demonstrated the important role of m6A modification in human glioblastoma development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE93054 | GEO | 2017/03/28

SECONDARY ACCESSION(S): PRJNA360051

REPOSITORIES: GEO

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The m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-Like Cells by Sustaining FOXM1 Expression and Cell Proliferation Programing

Project description:The dynamic and reversible N6-methyladenosine (m6A) RNA modification installed and erased by N6-methyltransferases and demethylases regulates gene expression and cell fate. Here, we show that the m6A demethylase ALKBH5 is highly expressed in glioblastoma stem-like cells (GSCs). Silencing ALKBH5 suppresses the proliferation of patient-derived GSCs in vitro and in vivo. Integrated transcriptome and m6A-seq analyses revealed altered expression of select ALKBH5 target genes, including FOXM1, a critical transcription factor for the ALKBH5-dependent cell cycle gene expression. ALKBH5 binds to and demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression. Further, a long noncoding RNA antisense to the FOXM1 (FOXM1-AS) interacts with ALKBH5 and FOXM1 nascent transcripts and promotes their interaction. Depleting ALKBH5 and FOXM1-AS disrupted GSC tumorigenesis through the FOXM1 axis. Our work uncovers a novel function for ALKBH5 in maintaining GSC tumorigenicity and provides insight into critical roles of the m6A RNA methylation in human brain tumor.

2017-03-28 | GSE87515 | GEO

Arabidopsis Messenger RNA N6-methyladenosine Demethylation Regulates Plant Development

Project description:N6-methyladenosine (m6A) is the most abundant internal modification in the messenger RNA (mRNA) of all higher eukaryotes. This modification has been shown to be reversible in mammals; it is installed by a methyltransferase heterodimer complex of METTL3 and METTL14 bound with WTAP, and reversed by iron(II)- and Î±-ketoglutarate-dependent demethylases FTO and ALKBH5. This modification exhibits significant functional roles in various biological processes. The m6A modification as a RNA mark is recognized by reader proteins, such as YTH domain family proteins and HNRNPA2B1; m6A can also act as a structure switch to affect RNA-protein interactions for biological regulation. In Arabidopsis thaliana, the methyltransferase subunit MTA (the plant orthologue of human METTL3, encoded by At4g10760) was well characterized and FIP37 (the plant orthologue of human WTAP) was first identified as the interacting partner of MTA. Here we report the discovery and characterization of reversible m6A methylation mediated by AtALKBH10B (encoded by At4g02940) in A. thaliana, and noticeable roles of this RNA demethylase in affecting plant development and floral transition. Our findings reveal potential broad functions of reversible mRNA methylation in plants. m6A peaks were identified from wild type Columbia-0 and atalkbh10b-1 mutant in two biological replicates

2016-03-24 | E-GEOD-79523 | biostudies-arrayexpress

ALKBH5 impacts malignancy of hepatocellular carcinoma via m6A-mediated epigenetic modulation

Project description:N6-methyladenosine (m6A) modification is implicated in the tumorigenicity of hepatocellular carcinoma (HCC). AlkB homolog 5 (ALKBH5) is one of the m6A demethylases, and it has not been well characterized in HCC. In our study we clarify the biological roles and potential mechanisms of ALKBH5 in HCC. We identify the expression profile of ALKBH5 in HCC and find that it serves as an independent prognostic factor of HCC survival. It impacts the proliferation and invasion capability of HCC cells in vitro and in vivo. ALKBH5-mediated m6A demethylation leads to a post-transcriptional modulation of LYPD1. In addition, we reveal the tumor-related behaviors of LYPD1.

2020-08-11 | GSE149510 | GEO

ALKBH5 is a New Mammalian RNA Demethylase

Project description:N6-methyladenosine (m6A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as a new mammalian demethylase that oxidatively removes the m6A modification in mRNA in vitro and inside cells. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1552 differentially expressed genes which cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. We show that Alkbh5-deficiency impacts the expression levels of some of these mRNAs, supporting the observed phenotype. The discovery of this new RNA demethylase strongly suggests that the reversible m6A modification plays fundamental and broad functions in mammalian cells. RNA-seq in two cell types

2013-02-15 | E-GEOD-40132 | biostudies-arrayexpress

ALKBH5 Induces Fibroblast-to-Myofibroblast Transformation During Hypoxia to Protect Against Cardiac Rupture After Myocardial Infarction

Project description:Objectives: To investigate the role of ALKBH5 in fibroblasts during post-myocardial infarction (MI) repair. Background: N6-methyladenosine (m6A) mRNA modification has been shown to play an important role in cardiovascular diseases. The RNA demethylase, AlkB homolog 5 (ALKBH5), is an m6A "eraser" that is responsible for decreased m6A methylation. However, its role in cardiac fibroblasts during the post-MI healing process remains elusive. Methods: MI was mimicked by permanent left anterior descending artery ligation in global ALKBH5-knockout, ALKBH5-knockin, and fibroblast-specific ALKBH5-knockout mice to study the function of ALKBH5 during post-MI collagen repair. Methylated RNA immunoprecipitation sequencing was performed to explore potential ALKBH5 targets. Results: Dramatic alterations in ALKBH5 expression were observed during the early stage post-MI and in hypoxic fibroblasts. Global ALKBH5 knockin reduced infarct size and improved cardiac function after MI. The global and fibroblast-specific ALKBH5-knockout mice both exhibited low survival rates along with poor collagen repair, impaired cardiac function, and cardiac rupture. Both in vivo and in vitro ALKBH5 loss led to impaired fibroblast activation and decreased collagen deposition. Additionally, hypoxia, but not TGF-β1 or Ang II, upregulated ALKBH5 expression in myofibroblasts in a HIF-1α-dependent transcriptional manner. Mechanistically, ALKBH5 promoted the stability of ErbB4 mRNA and the degradation of ST14 mRNA via m6A demethylation. Fibroblast-specific ErbB4 overexpression ameliorated the impaired fibroblast-to-myofibroblast transformation and poor post-MI repair due to ALKBH5 knockout. Conclusions: Fibroblast ALKBH5 positively regulates post-MI healing via post-transcriptional modification and stabilization of ErbB4 mRNA in an m6A-dependent manner. Targeting ALKBH5/ERBB4 may be a potential therapeutic option for post-MI cardiac rupture.

2023-10-01 | GSE226415 | GEO

The N6-methyadenosine (m6A) levels in PC9 cell lines.

Project description:ALKBH5 (AlkB homolog 5) has been identified as a eukaryotic demethylase, which catalyzes N6 adenosine. N6-methyladenosine (m6A) is oxidatively demethylated by ALKBH5 with α-ketoglutarate as a substrate and Fe (II) as a coenzyme. We used microarrays to detail the differential gene expression by ALKBH5 knockdown in lung cancer cell lines.

2022-06-01 | GSE165454 | GEO

Expression data from lung cancer cell lines

2022-06-01 | GSE165453 | GEO

N6-methyladenosine mRNA Modification Is Essential for Human Pancreatic Lineage Specification [m6A-Seq]

Project description:Recent advances in pancreatic differentiation from human pluripotent stem cells (hPSCs) hold great potentials for disease modeling and regenerative medicine, and more precise control over the dynamic differentiation process is critical. N6-methyladenosine (m6A) is the most prevalent internal messenger RNA (mRNA) modification, while the roles of m6A mark in pancreatic differentiation and development remain elusive. In addition, ALKBH5 is a major mRNA m6A demethylase and its role in pancreatic differentiation has not been reported. Here, we firstly studied mRNA m6A dynamics during pancreatic differentiation from hPSCs. Next, using the CRISPR-based genome editing tool, we generated ALKBH5 knockout hPSC lines and found that ALKBH5 plays important roles in pancreatic specification. After that, we conducted a series of functional and mechanistic studies, and demonstrated that ALKBH5 modulated many important genes involved in pancreatic differentiation. Collectively, our findings identified ALKBH5 as an essential regulator of human pancreatic differentiation and highlighted that m6A modification presents a new layer of regulation at epitranscriptome levels during cell-fate specification.

2022-06-13 | GSE163963 | GEO

N6-methyladenosine mRNA Modification Is Essential for Human Pancreatic Lineage Specification [RNA-Seq]

2022-06-13 | GSE163945 | GEO

ALKBH5 facilitates the progression of skin cutaneous melanoma through promoting ABCA1 demethylation and inhibiting autophagy in an m6A-dependent manner

Project description:Background: N6-methyladenosine (m6A) is the most common and abundant mRNA modification, playing an essential role in biological processes and tumor development. However, the role of m6A methylation in skin cutaneous melanoma (SKCM) is not yet clear. This study analyzed the expression of m6A-related functional genes in SKCM and aimed to explore the key demethylase ALKBH5 mediated m6A modification and its potential mechanism in human SKCM. Methods: Based on public databases, the m6A-related gene expression landscape in SKCM was portrayed. MeRIP-Seq and RNA-Seq were used to recognize the downstream target of ALKBH5. In vivo and in vitro functional phenotype and rescue functional experiments were performed to explore the mechanism of the ALKBH5-ABCA1 axis in SKCM. Results: We found ALKBH5 upregulated in SKCM, associated with poor prognosis. ALKBH5 can promote melanoma cell proliferation, colony formation, migration, and invasion and inhibit autophagy in vitro, facilitating tumor growth and metastasis in vivo. We identified ABCA1, a membrane protein that assists cholesterol efflux, as a downstream target of ALKBH5-mediated m6A demethylation. Finally, our data demonstrated that ALKBH5 promoted SKCM via mediating ABCA1 downregulation by reducing ABCA1 mRNA stability in an m6A-dependent manner. Conclusion: Our findings exhibited the functional value of the key demethylase ALKBH5 mediated m6A modification in the progression of SKCM, suggesting ALKBH5 and its target ABCA1 as potential therapeutic targets in SKCM.

2024-02-29 | GSE253795 | GEO

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