Next Generation Sequencing Facilitates Quantitative Analysis of mRNA lifetime of Wild Type and Mettl3-/- mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE108330 | GEO | 2019/04/02
REPOSITORIES: GEO
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Project description:Considering m6A modification in mRNA was reported to be intensively corelated with RNA metabolism like RNA decay and RNA translation, we wonderd whether deleting Mettl3, the main catalzing enzyme, affect the RNA translation efficiency of mouse dendritic cells.
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Project description:Hematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation according to physiological demands, but how different facets of these functions are precisely regulated is not fully understood. N6-methyladenosine (m6A) mRNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deleting the m6A methyltransferase, Mettl3, from the adult hematopoietic system led to an accumulation of HSCs in the bone marrow and marked reduction of HSC reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not have any discernable impact on myeloid cell number or function. m6A sequencing on purified HSCs revealed 2,073 genes with significant m6A modification. In particular, Myc, a key regulator of HSC differentiation, was identified as a direct target of m6A in HSCs. Mettl3-deficient HSCs failed to up-regulate Myc expression upon stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3-deficient HSCs. Our results thus revealed a key role of m6A in governing HSC differentiation by regulating Myc expression. This data includes m6A sequencing data on HSCs from wild-type or Mettl3-deficient mice, revealing the Mettl3-depedent m6A targets in HSCs.
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Project description:We observe the increase of stress resilience in Drosophila in which the m6A methyltransferase Mettl3 is knocked down. Mettl3-dependent m6A is present in the 5' UTR of genes enriched for neurogenesis and signaling pathways, and determine that Mettl3-dependent m6A regulates the decay of heat shock chaperones. Expression levels of genes with Mettl3-dependent m6A are increased with the reduction of Mettl3 and with heat shock stress in the brain.
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Project description:N6-methyladenosine (m6A) methylation of mRNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms’ tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the mechanism of MTC assembly remains elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3), that is highly expressed in breast cancer. Furthermore, we find that both METTL3a and full-length METTL3 are required for MTC assembly, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is required for METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC assembly. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A methylation, and METTL3a mediates mTOR activation via m6A-mediated suppression of TMEM127 expression. Consequently, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component for MTC assembly, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.
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Project description:Hematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation according to physiological demands, but how different facets of these functions are precisely regulated is not fully understood. N6-methyladenosine (m6A) mRNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deleting the m6A methyltransferase, Mettl3, from the adult hematopoietic system led to an accumulation of HSCs in the bone marrow and marked reduction of HSC reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not have any discernable impact on myeloid cell number or function. m6A sequencing on purified HSCs revealed 2,073 genes with significant m6A modification. In particular, Myc, a key regulator of HSC differentiation, was identified as a direct target of m6A in HSCs. Mettl3-deficient HSCs failed to up-regulate Myc expression upon stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3-deficient HSCs. Our results thus revealed a key role of m6A in governing HSC differentiation by regulating Myc expression. This data includes RNA-Seq analysis to showing only minor gene expression changes in adult bone marrow murine hematopoietic stem cells 10 days after Mettl3 deletion by pIpC administration compared to pIpC treated controls.
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Project description:METTL3 and METTL14 are considered to faithfully form the m6A writing complex in a 1:1 ratio, regulating the fate of mRNA by adding m6A modifications. However, recent studies have shown inconsistent expression and prognostic value of METTL3 and METTL14 in some tumors, suggesting that they may not be faithful in tumors. Pan-cancer analysis based on TCGA data reveals significant differences in expression, function, tumor burden correlation, and immune correlation between METTL3 and METTL14, especially in esophageal squamous cell carcinoma (ESCC). Knockdown of METTL3 significantly inhibits the cell proliferation in vitro and in vivo in ESCC EC109 cells, while the impact of METTL14 knockdown on proliferation is limited, and it cannot abolish the expression of METTL3 protein. mRNA-seq results indicate that METTL3 independently regulates the expression of 1615 genes, while only 776 genes are co-regulated by METTL3 and METTL14. Furthermore, through immunofluorescence co-localization, it is observed that METTL3 and METTL14 have certain inconsistencies in cellular localization. HPLC-MS results show that METTL3 independently binds to the Nop56p-associated pre-rRNA complex and mRNA splicing complex, separate from METTL14. Through bioinformatics and various omics studies, we have preliminarily discovered that METTL3 independently regulating tumor cell proliferation, and the participation in mRNA splicing may be a critical molecular mechanism. Our study provides an experimental basis and theoretical foundation for further understanding of the m6A writing complex and tumor therapy targeting METTL3.
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Project description:Genomic and transcriptomic alterations are insufficient to explain the variance in protein expression seen in cancer. Recent evidence has highlighted the role of N6-methyladenosine (m6A) in the regulation of mRNA expression, stability and translation, supporting a potential role for post-transcriptional regulation mediated by m6A in cancer. Here we explore prostate cancer as an exemplar cancer and generate the first prostate m6A maps, and further examined how low levels of N6-adenosine-methyltransferase (METTL3) associates with advanced prostate cancer and results in altered expression at the level of transcription, translation, and protein. In particular extracellular matrix proteins have a high number of m6A sites and show significant changes in expression with METTL3 knock-down. We also discovered the upregulation of a hepatocyte nuclear factor-driven gene signature that is associated with therapy resistance in prostate cancer. Significantly, METTL3 knock-down rendered the cells resistant to androgen receptor antagonists, implicating changes in m6A as a mechanism for therapy resistance in metastatic prostate cancer.
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