EIF4G2-dependent translation of pro-fibrotic mRNAs is essential for cardiac fibroblast activation (RIP-Seq)
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ABSTRACT:
PROVIDER: PRJNA1001026 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25482857_1.fastq.gz | Fastqsanger.gz | |||
| SRR25482857_2.fastq.gz | Fastqsanger.gz | |||
| SRR25482858_1.fastq.gz | Fastqsanger.gz | |||
| SRR25482858_2.fastq.gz | Fastqsanger.gz | |||
| SRR25482859_1.fastq.gz | Fastqsanger.gz |
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Project description:RNA-binding proteins control gene expression in cardiac fibroblasts during TGFb-driven fibrotic responses, including the eukaryotic translation initiation factor 4G2 (eIF4G2), which was known to facilitate alternative mRNA translation during cellular stresses. However, the precise role of eIF4G2 in cardiac fibroblast activation in response to fibrotic stress remains unclear. In this study, we found increased eIF4G2 protein levels in the hearts of heart failure patients and myocardial infarcted mice, as well as in TGFb-treated immortalized human and primary mouse cardiac fibroblasts. Depletion of eIF4G2 led to predominant translational downregulation of genes that are enriched in focal adhesion and extracellular matrix pathways. eIF4G2 knockdown reduced the proliferation, migration, and collagen secretion of TGFb-treated cardiac fibroblasts. Mechanistically, we found that the translation of IGFBP7 mRNA relies on eIF4G2, which is crucial for ECM production in response to pro-fibrotic stimuli. The interaction between eIF4G2 and a DEAD box RNA helicase DDX24 can regulate IGFBP7 protein expression in cardiac fibroblasts. Together, these findings suggest that the TGFb-eIF4G2-IGFBP7 axis establishes a novel translational regulatory circuit that governs cardiac fibroblast activation. Furthermore, conditional knockout of Eif4g2 in POSTN-positive myofibroblasts reduced cardiac fibrosis in the myocardial infarction mouse model, thus improving cardiac function. Our study provides insights into the molecular mechanism of eIF4G2-mediated translational regulation of crucial physiological mRNAs during cardiac fibroblast activation.
2024-07-31 | GSE239824 | GEO
Project description:RNA-binding proteins control gene expression in cardiac fibroblasts during TGFb-driven fibrotic responses, including the eukaryotic translation initiation factor 4G2 (eIF4G2), which was known to facilitate alternative mRNA translation during cellular stresses. However, the precise role of eIF4G2 in cardiac fibroblast activation in response to fibrotic stress remains unclear. In this study, we found increased eIF4G2 protein levels in the hearts of heart failure patients and myocardial infarcted mice, as well as in TGFb-treated immortalized human and primary mouse cardiac fibroblasts. Depletion of eIF4G2 led to predominant translational downregulation of genes that are enriched in focal adhesion and extracellular matrix pathways. eIF4G2 knockdown reduced the proliferation, migration, and collagen secretion of TGFb-treated cardiac fibroblasts. Mechanistically, we found that the translation of IGFBP7 mRNA relies on eIF4G2, which is crucial for ECM production in response to pro-fibrotic stimuli. The interaction between eIF4G2 and a DEAD box RNA helicase DDX24 can regulate IGFBP7 protein expression in cardiac fibroblasts. Together, these findings suggest that the TGFb-eIF4G2-IGFBP7 axis establishes a novel translational regulatory circuit that governs cardiac fibroblast activation. Furthermore, conditional knockout of Eif4g2 in POSTN-positive myofibroblasts reduced cardiac fibrosis in the myocardial infarction mouse model, thus improving cardiac function. Our study provides insights into the molecular mechanism of eIF4G2-mediated translational regulation of crucial physiological mRNAs during cardiac fibroblast activation.
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Project description:eIF4G2-dependent translation of pro-fibrotic mRNAs is essential for cardiac fibroblast activation
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Project description:eIF4G2-dependent translation of pro-fibrotic mRNAs is essential for cardiac fibroblast activation (Polysome-Seq)
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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:Learning and memory require activity-induced changes in dendritic translation, but which messenger RNAs (mRNAs) are involved and how they are regulated are unclear. Here, to monitor how depolarization impacts local dendritic biology, we employed a dendritically-targeted proximity labeling approach, followed by cross-linking immunoprecipitation (CLIP), ribosome profiling, and mass spectrometry. Depolarization of primary cortical neurons with KCl or the glutamate agonist DHPG causes rapid reprogramming of dendritic protein expression, where changes in dendritic mRNAs and proteins are weakly correlated. For a subset of pre-localized messages, depolarization increases translation of upstream open reading frames (uORFs) and their downstream coding sequences, enabling localized production of proteins involved in long term potentiation, cell signaling, and energy metabolism. This activity-dependent translation is accompanied by the phosphorylation and recruitment of the non-canonical translation initiation factor eIF4G2, and the translated uORFs are sufficient to confer depolarization-induced, eIF4G2-dependent translational control. These studies uncover an unanticipated mechanism by which activity-dependent uORF translational control by eIF4G2 couples activity to local dendritic remodeling.
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Project description:Learning and memory require activity-induced changes in mRNA translation within dendrites, but which mRNAs are involved and how they are regulated remain unclear. We combined proximity labeling with ribosome profiling and CLIP to monitor how depolarization impacts dendritic translation. For a functionally coherent set of transcripts highly enriched in mitochondrial genes, depolarization leads to enhanced uORF translation, eIF4G2 binding, and increased translation. Engineered reporters demonstrate that activity-dependent translational control is conferred by the 5’UTRs and that dendritic localization, eIF4G2 binding, and uORF translation are necessary and sufficient to mediate this regulation. Downstream, this drives activity-dependent changes in dendritic mitochondrial function. Our studies uncover an unanticipated mechanism by which activity-dependent uORF translational control by eIF4G2 enables the coupling of synaptic activity to local remodeling of dendrites.
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Project description:To investigate mRNAs binding with IGF2BP1 in HCC, we employed the RIP-seq
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Project description:Aberrant translation from mRNAs to proteins plays a crucial role in the pathogenesis of various cancers. Here, we revealed that the key proteins involved in translation were up-regulated in two hepatocellular carcinoma (HCC) cohorts. Specifically, we identified the translation initiation factor EIF4G2 as a marker of poor prognosis, linked to unfavorable overall survival (OS) outcomes. Our in vitro and in vivo studies confirmed that EIF4G2 promotes the development and metastasis of HCC. As an essential translation initiation factor, EIF4G2 knockdown disrupts polyribosome stability and inhibits nascent protein synthesis in the Huh-7 and MHCC97H cell lines. By com-paring the proteome and transcriptome of Huh-7 cells, we further identified PLEKHA1 as an essential target of EIF4G2 with IRES-dependent translation. PLEKHA1 was able to rescue the inhibitory effects of EIF4G2 knockdown on cell migration and invasion in both Huh-7 and MHCC97H cells. This research provides novel insights into the critical role of EIF4G2-dependent translation in cancer, where PLEKHA1 promotes HCC progression.
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Project description:To identify the target mRNAs of the m6A reader proteins YTHDF1 and YTHDF2, we carried out anti-YTHDF1 and anti-YTHDF2 RNA Immunoprecipitation (RIP) followed by RNA-sequencing. Using EZ-Magna RIP™ RNA-Binding Protein Immunoprecipitation Kit (Millipore), RNA from E12.5 wild-type mouse cortices and P0 wild-type mouse retinas was pulled down by rabbit polyclonal anti-YTHDF1 (proteintech) and rabbit polyclonal anti-YTHDF2 (proteintech), and then sequenced on Illumina HiSeq3000 platform. The filtered reads were mapped to the mouse reference genome (GRCm38) using STAR v2.5 with default parameters. The resulting bam files were fed to the HTSeq tool to count the number of RNA-seq reads, which was further normalized to calculate FPKM. To determine which gene is enriched, we computed the FPKM from RIP elute to input, and any fold change greater than 2 was considered enriched. From the embryonic cortex, we identified 986 and 1860 mRNAs by anti-YTHDF1 and anti-YTHDF2 RIP-seq, respectively. Anti-YTHDF1 and anti-YTHDF2 RIP-seq in mouse retina identified 2969 and 1638 mRNAs, respectively. This study provides the gene lists which show mRNAs binding with YTHDF1 and YTHDF2 in the mouse cortex and retina.
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