Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms
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ABSTRACT:
PROVIDER: PRJNA816271 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18328822_1.fastq.gz | Fastqsanger.gz | |||
| SRR18328822_2.fastq.gz | Fastqsanger.gz | |||
| SRR18328823_1.fastq.gz | Fastqsanger.gz | |||
| SRR18328823_2.fastq.gz | Fastqsanger.gz | |||
| SRR18328824_1.fastq.gz | Fastqsanger.gz |
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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:METTL3 catalyzes N6-methyladenosine (m6A) on mRNA, regulating RNA metabolism, but its role in early retinal development remains virtually unstudied. Using stem cell-derived 3D retinal organoids to model retinal progenitor cell (RPC) differentiation, we found that loss of METTL3 nuclear m6A enzymatic activity impairs formation of the Rx+ retinal anlage in vitro. Through dCas13b-FTO m6A engineering, we demonstrate that m6A modifications at the Six3 3'UTR control its stability. While Mettl3 loss altered histone modifications, direct METTL3 chromatin targets were not transcriptionally functional. Integration of transcriptome-wide m6A and protein-RNA mapping with a degron-based strategy revealed immediate effects of METTL3 degradation in RPCs, uncovering a regulatory interaction between METTL3 and its RNA target Ythdf1. We demonstrate uncoupling of chromatin accessibility from changes in retinal transcription and m6A modifications. In vivo studies of Mettl3-deficient RPCs showed altered cell cycle and impaired retinal ganglion cell generation. Our findings establish METTL3-dependent m6A modifications as an essential post-transcriptional layer that drives retinal development.
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Project description:METTL3 catalyzes N6-methyladenosine (m6A) on mRNA, regulating RNA metabolism, but its role in early retinal development remains virtually unstudied. Using stem cell-derived 3D retinal organoids to model retinal progenitor cell (RPC) differentiation, we found that loss of METTL3 nuclear m6A enzymatic activity impairs formation of the Rx+ retinal anlage in vitro. Through dCas13b-FTO m6A engineering, we demonstrate that m6A modifications at the Six3 3'UTR control its stability. While Mettl3 loss altered histone modifications, direct METTL3 chromatin targets were not transcriptionally functional. Integration of transcriptome-wide m6A and protein-RNA mapping with a degron-based strategy revealed immediate effects of METTL3 degradation in RPCs, uncovering a regulatory interaction between METTL3 and its RNA target Ythdf1. We demonstrate uncoupling of chromatin accessibility from changes in retinal transcription and m6A modifications. In vivo studies of Mettl3-deficient RPCs showed altered cell cycle and impaired retinal ganglion cell generation. Our findings establish METTL3-dependent m6A modifications as an essential post-transcriptional layer that drives retinal development.
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Project description:METTL3 catalyzes N6-methyladenosine (m6A) on mRNA, regulating RNA metabolism, but its role in early retinal development remains virtually unstudied. Using stem cell-derived 3D retinal organoids to model retinal progenitor cell (RPC) differentiation, we found that loss of METTL3 nuclear m6A enzymatic activity impairs formation of the Rx+ retinal anlage in vitro. Through dCas13b-FTO m6A engineering, we demonstrate that m6A modifications at the Six3 3'UTR control its stability. While Mettl3 loss altered histone modifications, direct METTL3 chromatin targets were not transcriptionally functional. Integration of transcriptome-wide m6A and protein-RNA mapping with a degron-based strategy revealed immediate effects of METTL3 degradation in RPCs, uncovering a regulatory interaction between METTL3 and its RNA target Ythdf1. We demonstrate uncoupling of chromatin accessibility from changes in retinal transcription and m6A modifications. In vivo studies of Mettl3-deficient RPCs showed altered cell cycle and impaired retinal ganglion cell generation. Our findings establish METTL3-dependent m6A modifications as an essential post-transcriptional layer that drives retinal development.
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Project description:METTL3 catalyzes N6-methyladenosine (m6A) on mRNA, regulating RNA metabolism, but its role in early retinal development remains virtually unstudied. Using stem cell-derived 3D retinal organoids to model retinal progenitor cell (RPC) differentiation, we found that loss of METTL3 nuclear m6A enzymatic activity impairs formation of the Rx+ retinal anlage in vitro. Through dCas13b-FTO m6A engineering, we demonstrate that m6A modifications at the Six3 3'UTR control its stability. While Mettl3 loss altered histone modifications, direct METTL3 chromatin targets were not transcriptionally functional. Integration of transcriptome-wide m6A and protein-RNA mapping with a degron-based strategy revealed immediate effects of METTL3 degradation in RPCs, uncovering a regulatory interaction between METTL3 and its RNA target Ythdf1. We demonstrate uncoupling of chromatin accessibility from changes in retinal transcription and m6A modifications. In vivo studies of Mettl3-deficient RPCs showed altered cell cycle and impaired retinal ganglion cell generation. Our findings establish METTL3-dependent m6A modifications as an essential post-transcriptional layer that drives retinal development.
2025-01-25 | GSE287484 | GEO
Project description:METTL3 catalyzes N6-methyladenosine (m6A) on mRNA, regulating RNA metabolism, but its role in early retinal development remains virtually unstudied. Using stem cell-derived 3D retinal organoids to model retinal progenitor cell (RPC) differentiation, we found that loss of METTL3 nuclear m6A enzymatic activity impairs formation of the Rx+ retinal anlage in vitro. Through dCas13b-FTO m6A engineering, we demonstrate that m6A modifications at the Six3 3'UTR control its stability. While Mettl3 loss altered histone modifications, direct METTL3 chromatin targets were not transcriptionally functional. Integration of transcriptome-wide m6A and protein-RNA mapping with a degron-based strategy revealed immediate effects of METTL3 degradation in RPCs, uncovering a regulatory interaction between METTL3 and its RNA target Ythdf1. We demonstrate uncoupling of chromatin accessibility from changes in retinal transcription and m6A modifications. In vivo studies of Mettl3-deficient RPCs showed altered cell cycle and impaired retinal ganglion cell generation. Our findings establish METTL3-dependent m6A modifications as an essential post-transcriptional layer that drives retinal development.
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Project description:METTL3 catalyzes N6-methyladenosine (m6A) on mRNA, regulating RNA metabolism, but its role in early retinal development remains virtually unstudied. Using stem cell-derived 3D retinal organoids to model retinal progenitor cell (RPC) differentiation, we found that loss of METTL3 nuclear m6A enzymatic activity impairs formation of the Rx+ retinal anlage in vitro. Through dCas13b-FTO m6A engineering, we demonstrate that m6A modifications at the Six3 3'UTR control its stability. While Mettl3 loss altered histone modifications, direct METTL3 chromatin targets were not transcriptionally functional. Integration of transcriptome-wide m6A and protein-RNA mapping with a degron-based strategy revealed immediate effects of METTL3 degradation in RPCs, uncovering a regulatory interaction between METTL3 and its RNA target Ythdf1. We demonstrate uncoupling of chromatin accessibility from changes in retinal transcription and m6A modifications. In vivo studies of Mettl3-deficient RPCs showed altered cell cycle and impaired retinal ganglion cell generation. Our findings establish METTL3-dependent m6A modifications as an essential post-transcriptional layer that drives retinal development.
2025-01-25 | GSE287489 | GEO
Project description:METTL3 catalyzes N6-methyladenosine (m6A) on mRNA, regulating RNA metabolism, but its role in early retinal development remains virtually unstudied. Using stem cell-derived 3D retinal organoids to model retinal progenitor cell (RPC) differentiation, we found that loss of METTL3 nuclear m6A enzymatic activity impairs formation of the Rx+ retinal anlage in vitro. Through dCas13b-FTO m6A engineering, we demonstrate that m6A modifications at the Six3 3'UTR control its stability. While Mettl3 loss altered histone modifications, direct METTL3 chromatin targets were not transcriptionally functional. Integration of transcriptome-wide m6A and protein-RNA mapping with a degron-based strategy revealed immediate effects of METTL3 degradation in RPCs, uncovering a regulatory interaction between METTL3 and its RNA target Ythdf1. We demonstrate uncoupling of chromatin accessibility from changes in retinal transcription and m6A modifications. In vivo studies of Mettl3-deficient RPCs showed altered cell cycle and impaired retinal ganglion cell generation. Our findings establish METTL3-dependent m6A modifications as an essential post-transcriptional layer that drives retinal development.
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Project description:METTL3 catalyzes N6-methyladenosine (m6A) on mRNA, regulating RNA metabolism, but its role in early retinal development remains virtually unstudied. Using stem cell-derived 3D retinal organoids to model retinal progenitor cell (RPC) differentiation, we found that loss of METTL3 nuclear m6A enzymatic activity impairs formation of the Rx+ retinal anlage in vitro. Through dCas13b-FTO m6A engineering, we demonstrate that m6A modifications at the Six3 3'UTR control its stability. While Mettl3 loss altered histone modifications, direct METTL3 chromatin targets were not transcriptionally functional. Integration of transcriptome-wide m6A and protein-RNA mapping with a degron-based strategy revealed immediate effects of METTL3 degradation in RPCs, uncovering a regulatory interaction between METTL3 and its RNA target Ythdf1. We demonstrate uncoupling of chromatin accessibility from changes in retinal transcription and m6A modifications. In vivo studies of Mettl3-deficient RPCs showed altered cell cycle and impaired retinal ganglion cell generation. Our findings establish METTL3-dependent m6A modifications as an essential post-transcriptional layer that drives retinal development.
2025-01-25 | GSE287485 | GEO
Project description:METTL3 catalyzes N6-methyladenosine (m6A) on mRNA, regulating RNA metabolism, but its role in early retinal development remains virtually unstudied. Using stem cell-derived 3D retinal organoids to model retinal progenitor cell (RPC) differentiation, we found that loss of METTL3 nuclear m6A enzymatic activity impairs formation of the Rx+ retinal anlage in vitro. Through dCas13b-FTO m6A engineering, we demonstrate that m6A modifications at the Six3 3'UTR control its stability. While Mettl3 loss altered histone modifications, direct METTL3 chromatin targets were not transcriptionally functional. Integration of transcriptome-wide m6A and protein-RNA mapping with a degron-based strategy revealed immediate effects of METTL3 degradation in RPCs, uncovering a regulatory interaction between METTL3 and its RNA target Ythdf1. We demonstrate uncoupling of chromatin accessibility from changes in retinal transcription and m6A modifications. In vivo studies of Mettl3-deficient RPCs showed altered cell cycle and impaired retinal ganglion cell generation. Our findings establish METTL3-dependent m6A modifications as an essential post-transcriptional layer that drives retinal development.
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