Mettl4 limits the proliferation and differentiation of neural stem cells via regulating RNA alternative splicing
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ABSTRACT:
PROVIDER: PRJNA877577 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21461821_1.fastq.gz | Fastqsanger.gz | |||
| SRR21461821_2.fastq.gz | Fastqsanger.gz | |||
| SRR21461822_1.fastq.gz | Fastqsanger.gz | |||
| SRR21461822_2.fastq.gz | Fastqsanger.gz | |||
| SRR21461823_1.fastq.gz | Fastqsanger.gz |
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Project description:Previous studies indicate that Mettl4 regulates gene expression and RNA splicing. However, the biological functions of METTL4 remain unclear. Here we show that the absence of Mettl4 leads to sub lethality in mouse and promotes brain function in processing learning and working memory. The neural stem cells in subgranular zone are more proliferative in Mettl4 knockout mice compared with wild type mice. The proliferation and neurogenesis of primary neural stem cells are increased in the absence of Mettl4. Meanwhile, Mettl4 knockout NSCs are more sensitive low levels of H2O2, which is known to promote proliferation and neurogenesis of neural stem cells. The biological effects caused could be due to the altered gene expression or alternative splicing in neural stem cells when Mettl4 is absent. To investigate the effects at transcriptome level, we performed RNA sequencing.
2023-09-30 | GSE212821 | GEO
Project description:We compare mettl4 KO and WT samples from different species to understand how mettl4 affects the alterative splicing
2023-06-01 | GSE178511 | GEO
Project description:METTL4 belongs to a subclade of MT-A70 family members of methyltransferase (MTase) proteins and has been shown to mediate N6-adenosine methylation for both RNA and DNA in diverse eukaryotes. Here, we analysed differentially expressed genes and different alternatively splicing genes compared to the mutant and wild-type by RNA-seq, we found that METTL4 can regulate pre-mRNA alternative splicing.
2022-10-21 | GSE190241 | GEO
Project description:N6-methylation of 2’-O-methyladenosine (Am) in RNA occurs in eukaryotic cells to generate N6,2’-O-dimethyladenosine (m6Am). Identification of the methyltransferase responsible for m6Am catalysis has accelerated studies on the function of m6Am in RNA processing. While m6Am is generally found in the first transcribed nucleotide of mRNAs, the modification is also found internally within U2 snRNA. However, the writer required for catalyzing internal m6Am formation had remained elusive. By sequencing transcriptome-wide RNA methylation at single-base-resolution, we identified human METTL4 as the writer that directly methylates Am at U2 snRNA position 30 into m6Am. We found that METTL4 localizes to the nucleus and its conserved methyltransferase catalytic site is required for U2 snRNA methylation. By sequencing human cells with overexpressed Mettl4, we determined METTL4’s in vivo target RNA motif specificity. In the absence of Mettl4 in human cells, U2 snRNA lacks m6Am thereby affecting a subset of splicing events that exhibit specific features such as overall 3’ splice-site weakness with certain motif positions more affected than others. This study establishes that METTL4 methylation of U2 snRNA regulates splicing of specific pre-mRNA transcripts.
2020-08-17 | GSE144745 | GEO
Project description:BACKGROUND: Mitochondrial dysfunction is a key factor in the development of atherogenesis. Methyltransferase-like protein 4 (METTL4) mediates N6-deoxyadenosine (6mA) methylation of mammalian mitochondrial DNA (mtDNA). However, the role of METTL4-mediated mitoepigenetic regulation in atherosclerosis is still unknown. This study aims to investigate the potential involvement of METTL4 in atherosclerosis, explore the underlying mechanism, and develop targeted strategies for treating atherosclerosis. METHODS: Expression levels of mtDNA 6mA and METTL4 were determined in atherosclerotic lesions. We explored the mechanism of METTL4 involvement in atherosclerosis using Mettl4Mac-KO-Apoe-/- and Mettl4MUT-Apoe-/- mice and cell models, as well as bone marrow transplantation. Natural compound libraries were screened to identify potent METTL4 antagonists. In addition, bioinspired proteolysis-targeting (PROTAC) technology targeting macrophages within plaques was used to increase the efficacy of the METTL4 antagonist. RESULTS: The expression levels of mtDNA 6mA and METTL4 were significantly increased in plaque macrophages. Mettl4Mac-KO-Apoe-/- mice displayed suppressed mtDNA 6mA levels and atherosclerotic progression, which were reversed by METTL4 restoration via bone marrow transplantation (n = 6). Mechanistically, elevated METTL4 expression reduces MT-ATP6 expression by suppressing its transcription, thereby impairing the activity of mitochondrial respiration chain complex V. This disruption leads to the accumulation of excess protons in the mitochondrial intermembrane space, causing mitochondrial dysfunction. Consequently, mtDNA is released into the cytoplasm, ultimately triggering inflammasome activation. All results were reversed by the mutation in the METTL4 methyltransferase active site. Mettl4MUT-Apoe-/- mice showed suppressed mtDNA 6mA levels and atherosclerotic progression, and repaired mitochondrial function of macrophage, which were reversed by METTL4 restoration via bone marrow transplantation (n = 6). Pemetrexed (PEM) was identified as the first METTL4 antagonist to effectively alleviate atherosclerotic progression. Furthermore, we generated a proteolysis-targeting chimera drug based on PEM (PROTAC-PEM) that specifically targeting METTL4 in macrophages within plaques, showing a promising therapeutic effect on atherosclerosis. CONCLUSIONS: This study revealed a novel mechanism by which mtDNA 6mA orchestrated mitochondrial function-related gene expression in macrophages, thereby promoting atherosclerosis. Through various experimental techniques, such as gene manipulation, pharmacological inhibition and PROTAC, this study demonstrated that mtDNA 6mA and its specific enzyme METTL4 hold potential as therapeutic targets for atherosclerosis.
2024-11-02 | GSE280434 | GEO
Project description:Investigation of mettl4 mediated alterative splicing variation
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Project description:We identified U2 as the substrate of mettl4 in fly
2020-04-30 | GSE143958 | GEO
Project description:RBM5, a regulator of alternative splicing of apoptotic genes, and its close homologues, RBM6 and RBM10, are RNA binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation and its modulation recapitulates or antagonizes the effects of RBM5, 6 and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation. RNA from 3 biological replicates of knockdowns of RBM5, 6 and 10 and a control set were used. Changes between the control and knockdowns were measured based on using a splice-junction array (Affymetrix HJAY).
2013-12-20 | E-GEOD-47431 | biostudies-arrayexpress
Project description:RBM5, a regulator of alternative splicing of apoptotic genes, and its close homologues, RBM6 and RBM10, are RNA binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation and its modulation recapitulates or antagonizes the effects of RBM5, 6 and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation. CLIP-Seq analysis of RBM5, RBM6 and RBM10, with 2 biological replicates and one non-specific control for each protein.
2013-12-20 | E-GEOD-48066 | biostudies-arrayexpress
Project description:RBM5, a regulator of alternative splicing of apoptotic genes, and its close homologues, RBM6 and RBM10, are RNA binding proteins frequently deleted or mutated in lung cancer. We report that RBM5/6 and RBM10 antagonistically regulate the proliferative capacity of cancer cells and display distinct positional effects in alternative splicing regulation. We identify the Notch pathway regulator NUMB as a key target of these factors in the control of cell proliferation. NUMB alternative splicing, which is frequently altered in lung cancer, can regulate colony and xenograft tumor formation and its modulation recapitulates or antagonizes the effects of RBM5, 6 and 10 in cell colony formation. RBM10 mutations identified in lung cancer cells disrupt NUMB splicing regulation to promote cell growth. Our results reveal a key genetic circuit in the control of cancer cell proliferation.
2013-12-20 | GSE47431 | GEO