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Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms

ABSTRACT: Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms

PROVIDER: PRJNA816271 | ENA |

REPOSITORIES: ENA

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Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms

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

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METTL3 promotes translation in human cancer cells

Project description:we find METTL3 associates with polyribosomes and promotes translation. METTL3 depletion inhibits translation, and both wild-type and catalytically inactive METTL3 promote translation when tethered to the 3' untranslated region (UTR) of a reporter mRNA. Mechanistically, METTL3 enhances mRNA translation through an interaction with the translation initiation machinery. m6A seq in A549 and H1299 cells, RNA seq in METTL3 knockdown cells

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CCR3 knockdown attenuates prolonged underwater operation-induced cognitive impairment via alleviating microglia-mediated neuroinflammation

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METTL3 KD in HepG2 cells

Project description:To gain insight into possible processes that require m6A for their function, METTL3 was knocked down (KD) in HepG2 cells by siRNA transfections Differential expression analysis of METTL3 KD versus mock-transfected HepG2 cells, in 2 biological replicates

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Binding motif analysis of METTL3，WTAP in METTL3，WTAP overexpressed Human 293T cells

Project description:label the cells overexpressed Myc tagged METTL3 and Flag tagged WTAP with 4-SU, the RNA bound by METT3,WTAP can be got by Myc or Flag IP followed by RNA isolation by using the TRIzol (Invitrogen) reagent by following the company manual.the RNA was then used for library preparation using a TruSeq™ RNA Sample Prep Kit v2 (Illumina, San Diego, CA, USA) according to the manufacturer’s protocol.The libraries were sequenced using HiSeq2000 (Illumina) in single-read mode, creating reads with a length of 50 bp. Sequencing chemistry v2 (Illumina) was used and samples were multiplexed in two samples per lane. discovery of the binding motif of METTL3，WTAP in METTL3，WTAP overexpressed Human 293T cells

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Mettl3-dependent m6A modulation of mRNAs in the Drosophila brain attenuates the stress response

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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.

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Project description:N6-methyladenosine (m6A) reader Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) participates in the initiation and growth of cancers by communicating with various targets. Here, we found IGF2BP2 is highly expressed in T-ALL. Gain and loss of IGF2BP2 demonstrated IGF2BP2 was essential for T-ALL cell proliferation in vitro and loss of IGF2BP2 prolonged animal survival in a human T-ALL xenograft model. Mechanistically, IGF2BP2 directly bound to T-ALL oncogene NOTCH1 via an m6A dependent manner.

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