LINC01963 Promotes Pancreatic Cancer Proliferation via METTL3/IGF2BP2 Axis-Mediated m6A Modification of c-Myc
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1253648 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33241215_1.fastq.gz | Fastqsanger.gz | |||
| SRR33241215_2.fastq.gz | Fastqsanger.gz | |||
| SRR33241216_1.fastq.gz | Fastqsanger.gz | |||
| SRR33241216_2.fastq.gz | Fastqsanger.gz | |||
| SRR33241217_1.fastq.gz | Fastqsanger.gz |
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Project description:C-Myc overexpression is an important molecular hallmark of pancreatic ductal adenocarcinoma (PDAC), but directly targeting c-Myc is extremely challenging. Identifying key upstream factors involved in c-Myc overexpression provides promising indirect targets for c-Myc. Herein, the long noncoding RNAs (lncRNAs) highly expressed in PDAC and significantly correlated with c-Myc expression were identified using RNA sequencing datasets. Among them, LINC01963 was found to interact with c-Myc, as confirmed by RNA pull-down and RIP-qPCR assays. Furthermore, high LINC01963 expression was correlated with poor PDAC prognosis, and functional studies demonstrated that its knockdown inhibited PDAC cell proliferation and xenograft tumor growth. Mechanistic studies identified LINC01963 as a key regulator of c-Myc stability, consequently affecting cell cycle through the c-Myc/p21-related signaling pathways. Further investigation revealed that LINC01963 enhanced N6-methyladenosine (m6A) modification of c-Myc mRNA by protecting methyltransferase-like 3 (METTL3) protein from KDM1B-mediated ubiquitin-proteasome degradation. Intriguingly, LINC01963 also stabilized c-Myc mRNA by facilitating the formation of a ternary complex with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and m6A-modified c-Myc. Our study reveals that LINC01963 promotes PDAC tumorigenesis through METTL3/IGF2BP2 axis-coordinated regulation of c-Myc, suggesting a new strategy for indirectly targeting c-Myc.
2025-04-29 | GSE295171 | GEO
Project description:Epigenetic changes present in many physiological and pathological processes. The N6-methyladenosine (m6A) modification is the most common modification in eukaryotic mRNA. However, the role of m6A modification in diabetic nephropathy (DN) is still elusive. Here, the level of m6A modification was significantly upregulated in podocytes stimulated by high glucose (HG), which was caused by elevated levels of METTL3. The results were consistent in the streptozotocin (STZ)-induced experimental model of type 1 diabetes and db/db type 2 diabetes mice. Knocking out METTL3 significantly reduced the inflammation and apoptosis of HG-stimulated podocytes, while its overexpression significantly aggravated these responses. More importantly, silencing METTL3 both in type 1 and type 2 diabetic mice in vivo significantly reduced urinary albumin excretion and histopathological injury. Mechanistically, METTL3 modulated Notch signaling via the m6A modification of its target gene, TIMP2, and exerted pro-inflammatory and pro-apoptotic effects. Moreover, METTL3 enhanced the stability of TIMP2 in an insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2)-dependent manner. In summary, this study suggested that METTL3-mediated m6A modification is an important mechanism of podocyte injury in DN. Targeting m6A through the writer enzyme METTL3 is a potential approach for the treatment of DN.
2024-12-08 | GSE190436 | GEO
Project description:The role of N6-methyladenosine (m6A) modifications in renal diseases is largely unknown. Here, we characterised the role of N6-adenosine-methyltransferase METTL3, whose expression is elevated in renal tubules in different acute kidney injury (AKI) models as well as in human biopsies and cultured tubular epithelial cells (TECs). METTL3 silencing alleviated renal inflammation and programmed cell death in TECs in response to stimulation by tumor necrosis factor alpha (TNF-α), cisplatin, and lipopolysaccharide (LPS), whereas METTL3 overexpression had the opposite effects. Conditional knockout (cKO) of METTL3 from mouse kidneys attenuated cisplatin- and ischemic/reperfusion (I/R)-induced renal dysfunction, injury, and inflammation. Moreover, TAB3 was identified as a target of METTL3 by m6A methylated RNA immunoprecipitation sequencing and RNA sequencing. The stability of TAB3 was increased through binding of IGF2BP2 to its m6A-modified stop codon regions. The pro-inflammatory effects of TAB3 were then explored both in vivo and in vitro. Adeno-associated virus 9 (AAV9)-mediated METTL3 silencing attenuated renal injury and inflammation in cisplatin- and LPS-induced AKI mouse models. We further identified Cpd-564 as a METTL3 inhibitor that had better protective effects against cisplatin- and I/R-induced renal injury and inflammation than S-adenosyl-L-homocysteine, a previously-identified METTL3 inhibitor. Collectively, METTL3 promoted m6A modification of TAB3 and enhanced its stability via IGF2BP2-dependent mechanisms. Both pharmacological and genetic inhibition of METTL3 attenuated renal injury and inflammation, suggesting that the METTL3/TAB3 axis is a potential target for treatment of AKI.
2023-12-15 | GSE198643 | GEO
Project description:N6-methyladenosine (m6A) RNA methylation is the most abundant modification on mRNAs and plays important roles in various biological processes. The formation of m6A is catalyzed by a methyltransferase complex including methyltransferase like 3 (METTL3) as a key factor. However, the in vivo functions of METTL3 and m6A modification in mammalian development remain unclear. Here we show that specific inactivation of Mettl3 in mouse nervous system causes severe developmental defects in the brain. Mettl3 conditional knockout mice manifest cerebellar hypoplasia caused by drastically enhanced apoptosis of new born cerebellar granule cells (CGCs) in the external granular layer (EGL). METTL3 depletion induced loss of m6A modification causes extended RNA half-lives and aberrant splicing events, consequently leading to dysregulation of transcriptome-wide gene expression and premature CGC death. Our findings reveal a critical role of METTL3-mediated m6A in regulating the development of mammalian cerebellum.
2018-07-15 | GSE100528 | GEO
Project description:To investigate the role of METTL3-mediated m6A modification, we performed m6A-sequencing to map the m6A modification in control or METTL3 knockdown BGC823 cells.
2019-10-29 | GSE133132 | GEO
Project description:N6-methyladenosine (m6A) is an abundant modification on mRNA, and plays critical functions in various cellular processes, including cell fate determination and lineage transition. However, the landscape and dynamics of m6A modification in haematopoietic system remain unknown. Here, we delineate a comprehensive m6A landscape across haematopoietic hierarchy and uncover that IGF2BP2 is required for preserving haematopoietic stem cells (HSCs) function. Our data reveal a marked cell-type- and haematopoietic-lineage-specific m6A landscape. Intriguingly, most m6A modifications arise in the early stat of haematopoiesis, and are critical in defining cellular states of HSCs. Moreover, m6A modification is the major factor in determining mRNA abundance in HSCs. Importantly, we find that higher expression of m6A reader IGF2BP2 is critical in controlling gene expression states and the functional maintenance of HSCs. IGF2BP2 deficiency induces apoptosis and quiescence loss, and substantially impairs the reconstitution capacity of HSCs. In addition, deletion of IGF2BP2 increases the mitochondrial activity of HSCs. Mechanistically, IGF2BP2 stabilizes Bmi1 mRNA in an m6A-dependent manner, which represses the expression of mitochondria-related genes. Collectively, our results present a fascinating portrait of m6A modification during haematopoiesis, and uncover a key role of IGF2BP2 in maintaining HSCs function by regulating Bmi1 stability and restraining mitochondrial activity.
2021-10-26 | GSE165863 | GEO
Project description:Here we determine the map of RNA methylation (m6A) in mouse embrionic stem cells, and Mettl3 knock out cells Examination of m6A modification sites on the transcriptome of mouse Embryonic stem cells and Embryonic Mettl3 knock out cells, using a m6A specific antibody.
2014-10-16 | E-GEOD-52662 | biostudies-arrayexpress
Project description:M6A modification plays a vital role in gestational diabetes mellitus (GDM) progression. However, the role of METTL3 and differential m6A-modified circRNAs in GDM stay to be investigated. Placental tissue samples from GDM patients and normal controls (NC) were collected to measure changes in m6A modification levels. MeRIP-seq on placental tissue was performed to detect differential m6A-modified circRNAs.High glucose (HG)-treated JEG3 cells were used to establish the GDM cell model. Differentially expressed circRNAs levels in GDM and NC groups was measured by qRT-PCR. We knocked down METTL3 to study its function. Additionally, we conducted functional recovery experiments. Dot blot assay was utilized to assess changes in m6A levels. MeRIP-qPCR was performed to evaluate the effect of knocking down METTL3 on m6A modification of hsa_circ_0072380 in JEG3 cells. Compared with NC group, GDM group exhibited increased levels of m6A modification and METTL3 expression. Differences in m6A modification of circRNAs exist between the GDM and NC groups. Hsa_circ_0000994, hsa_circ_0058733, and hsa_circ_0072380 were significantly down-regulated in GDM group while hsa_circ_0036376, hsa_circ_0000471, and hsa_circ_0001173 showed no significant differences between two groups. HG treatment promoted METTL3 expression and m6A level of JEG3 cells, and inhibited cell proliferation, migration, and invasion abilities. Knocking down METTL3 reversed these effects. After HG treatment, hsa_circ_0072380 was significantly down-regulated. Knocking down METTL3 led to up-regulation of hsa_circ_0072380, while knocking down hsa_circ_0072380 restored the function of SiMETTL3. Additionally, knocking down METTL3 significantly reduced m6A modification of hsa_circ_0072380. METTL3 mediated m6A modification of hsa_circ_0072380 to regulate GDM progression.
2024-12-16 | GSE250374 | GEO
Project description:The N6-methyladenosine (m6A) mRNA modification and the mitochondrial respiratory chain (MRC) hold paramount importance in the advancement of MASLD. This study thoroughly investigates the relationship and impact of m6A mRNA modification and mitochondrial function in the progression of MASLD. Here we report that the mRNA and protein levels of mitochondrial respiratory chain (MRC) subunits showed inconsistent trends in vivo experiments. Abnormal m6A modification and mitochondrial dysfunction in MASLD were attributed to the upregulation of methyltransferase like 3 (Mettl3) and the downregulation of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) induced by high-fat foods. Mettl3 promoted the MRC's function. However, knockout of the reader protein YTHDF1, which plays a crucial role in the m6A modification process, counteracted the effect of Mettl3 and suppressed MRC. In MASLD, damage to the MRC may be regulated by the Mettl3-m6A-YTHDF1 complex axis, especially by the role of YTHDF1. Our research has offered a novel perspective on the involvement of m6A mRNA methylation in the pathogenesis of MASLD.
2024-09-20 | PXD047819 | Pride
Project description:Background: N6-methyladenosine (m6A) RNA modification plays a crucial role in various biological events and is implicated in various metabolic-related diseases. However, its role in MASLD remains unclear. This study aims to investigate the impact of Mettl3 on MASLD through multi-omics analysis, with a focus on exploring its potential mechanisms of action. Methods: MASLD mouse models were established by feeding a high-fat diet for 12 weeks, and Mettl3 stable overexpression AML12 cell models were constructed via lentiviral transfection. Subsequent transcriptomic and proteomic analyses, as well as integrated analysis between different omics datasets, were conducted. Results: Mettl3 expression significantly increased in MASLD mouse models. In the transcriptomic and proteomic analyses, we identified 848 genes with significant inconsistencies between transcriptomic and proteomic datasets. GO/KEGG enrichment terms may involve post-transcriptional modifications, particularly Mettl3-mediated m6A modification. Subsequently, through integrated proteomic analysis of Mettl3-overexpressed AML12 cell models and MASLD mouse models, we selected the top 20 co-upregulated and co-downregulated GO/KEGG terms as the main biological processes influenced by Mettl3 in MASLD. By intersecting with pathways obtained from previous integrated analyses, we identified GO/KEGG terms affected by Mettl3-induced m6A modification. Protein-protein interaction analysis of proteins involved in these pathways highlighted GAPDH, ENO1, and TPI1 as three key hub genes. Conclusion: In MASLD, Mettl3 regulates the glycolytic pathway through m6A modification, influencing the occurrence and development of the disease via the key hub genes GAPDH, ENO1, and TPI1. These findings expand our understanding of MASLD and provide strong evidence for potential therapeutic targets and drug development.
2024-09-20 | PXD050565 | Pride