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The m6A reader IGF2BP2 regulates macrophage phenotypic activation and inflammatory diseases by stabilizing TSC1 and PPARγ

ABSTRACT: The m6A reader IGF2BP2 regulates macrophage phenotypic activation and inflammatory diseases by stabilizing TSC1 and PPARγ

PROVIDER: PRJNA680704 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13132477_1.fastq.gz	Fastqsanger.gz
	SRR13132477_2.fastq.gz	Fastqsanger.gz
	SRR13132478_1.fastq.gz	Fastqsanger.gz
	SRR13132478_2.fastq.gz	Fastqsanger.gz
	SRR13132479_1.fastq.gz	Fastqsanger.gz

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The m6A reader IGF2BP2 regulates macrophage phenotypic activation and inflammatory diseases by stabilizing TSC1 and PPARγ

Project description:Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Currently, little is known about how the intrinsic regulators modulate pro-inflammatory (M1) versus pro-healing (M2) macrophages activation. Here, we observed that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) -deleted macrophages exhibited enhanced M1 phenotype and promoted DSS induced colitis development. However, the IGF2BP2-/- macrophages were refractory to IL4 induced activation and alleviated cockroach extract induced pulmonary allergic inflammation. Molecular studies indicated IGF2BP2 switched M1 macrophages to M2 activation by targeting tuberous sclerosis 1 (TSC1) via an N6-methyladenosine-dependent manner. Additionally, we also showed a signal transducer and activators of transcription 6 (STAT6) - high mobility group AT-hook 2 (HMGA2) -IGF2BP2-peroxisome proliferator activated receptor-γ (PPARγ) axis involves in M2 macrophages differentiation. These findings highlight a key role of IGF2BP2 in regulation of macrophages activation and imply a potential therapeutic target of macrophages in the inflammatory diseases.

2021-03-15 | GSE162128 | GEO

IGF2BP2 induces subchondral bone loss of the temporomandibular joint via enhancing FOS-PPARγ-NFATC1 network

Project description:Overactivated osteoclastogenesis leading to abnormal subchondral bone loss is the main feature of temporomandibular joint osteoarthritis (TMJOA). The role of N6-methyladenosine (m6A) in osteoclast differentiation in TMJOA remains unknown. Here, we found that an m6A reader IGF2BP2 was essential for mature osteoclasts induction. In TMJ tissues of TMJOA patients, the expression of IGF2BP2 was increased. Moreover, IGF2BP2 was augmented in subchondral bone of monosodium iodoacetate (MIA)–induced TMJOA mice. Igf2bp2 deficiency attenuated MIA-induced subchondral bone loss and suppressed osteoclast differentiation. Mechanistically, IGF2BP2 directly stabilized PPARγ and C-FOS mRNA to enhance the NFATC1 signaling, thereby inducing osteoclast maturation. Moreover, the stabilized PPARγ promoted the transcription of C-FOS, resulting in a further amplified signaling of NFATC1. In Igf2bp2-deficient cells, overexpression of PPARγ and C-FOS rescued the function of osteoclasts through restoring reduced levels of NFATC1. On the other hand, IGF2BP2/PPARγ/C-FOS axis facilitated the formation of osteoclasts by restoring the inhibited autophagy levels through the downregulation of ATG16L2. Using an IGF2BP2 inhibitor CWI1-2 hindered osteoclast formation and represented therapeutic effects for TMJOA. In summary, IGF2BP2 is essential in differentiation and maturation of osteoclasts and aggravates TMJOA via stabilizing PPARγ and C-FOS, which promoting NFATC1-mediated osteoclast signaling and ATG16L2-mediated autophagy.

2025-02-24 | GSE282855 | GEO

Comment on: The m6A Reader IGF2BP2 Regulates Macrophage Phenotypic Activation and Inflammatory Diseases by Stabilizing TSC1 and PPARγ.

Project description:Recently, first insights into the regulation and the role of the RNA-binding protein IMP2 in macrophage activation have been published by Wang et al. This study addresses differences in the regulation of IMP2 between the human and murine system. While the expression of IMP2 in anti-inflammatory macrophages is synchronous in mice and men, IMP2 expression is regulated differently in inflammatory macrophages.

| S-EPMC8922093 | biostudies-literature

Inhibition of the m6A Reader IGF2BP2 as a Strategy against T-cell Acute Lymphoblastic Leukemia

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.

2022-09-15 | GSE205503 | GEO

The m6A Reader IGF2BP2 Regulates Glutamine Metabolism and Represents a Therapeutic Target in Acute Myeloid Leukemia [Ribo-seq]

Project description:We report that m6A reader IGF2BP2 participates in the regulation of glutamine metabolism in AML. To further clarify whether IGF2BP2 knockdown (KD) leads to translational inhibition, we perform Ribo-seq in control and IGF2BP2 KD cells.

2022-11-01 | GSE211618 | GEO

Inhibition of the m6A Reader IGF2BP2 as a Strategy against T-cell Acute Lymphoblastic Leukemia

Project description:T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant leukemia with extreme limited treatment for relapsed patients. 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. Furthermore, we identified a small-molecule IGF2BP2 inhibitor JX5 and treatment of T-ALL with JX5 showed similar functions as knockdown of IGF2BP2. These findings not only shed light on the role of IGF2BP2 in T-ALL, but also provide an alternative γ‑Secretase inhibitors (GSI) therapy to treat T-ALL.

2022-07-04 | GSE207323 | GEO

The m6A Reader IGF2BP2 Regulates Glutamine Metabolism and Represents a Therapeutic Target in Acute Myeloid Leukemia [RNA-seq]

Project description:We report that m6A reader IGF2BP2 participates in the regulation of glutamine metabolism in AML. Targeting IGF2BP2 with our developed inhibitor CWI1-2 shows promising therapeutic efficacy in AML.To explore the mechanism of the inhibitor, we performed RNA-seq in AML cells upon treatment with CWI1-2 or DMSO. On the other hand, to distinguish the mechanism between IGF2BP2 and YTHDF2, we compare RNA-seq data of IGF2BP2 KD with YTHDF2 KD.

2022-11-01 | GSE199204 | GEO

Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [IGF2BP2 RNA-seq]

Project description:Our data reveal that RNA m6A displays a sharp transition during leukemogenesis and involves in acquiring stem cell properties of leukemia stem cells (LSCs). We find that m6A reader IGF2BP2 and protein arginine methyltransferase PRMT6 play key roles in the acquisition of LSCs properties. Genetical deletion and pharmacological inhibition of PRMT6 delayed AML development. Mechanistically, IGF2BP2 regulates PRMT6 expression by stabilizing its mRNA in an m6A-dependent manner. PRMT6 further suppresses the expression of lipid transporter MFSD2A by establishing inactive H3R2me2a in its promoter region. Loss of PRMT6 and IGF2BP2 upregulates the expression of MFSD2A that increases the uptake of docosahexaenoic acid. Collectively, our findings uncover a critical role of IGF2BP2-PRMT6-MFSD2A signaling axis in AML development, and provide a promising therapeutic strategy for targeting LSCs.

2023-06-20 | GSE210278 | GEO

The m6A Reader IGF2BP2 Regulates Macrophage Phenotypic Activation and Inflammatory Diseases by Stabilizing TSC1 and PPAR<i>γ</i>.

Project description:Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Currently, little is known about how the intrinsic regulators modulate proinflammatory (M1) versus prohealing (M2) macrophages activation. Here, it is observed that insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 2 (IGF2BP2)-deleted macrophages exhibit enhanced M1 phenotype and promote dextran sulfate sodium induced colitis development. However, the IGF2BP2-/- macrophages are refractory to interleukin-4 (IL-4) induced activation and alleviate cockroach extract induced pulmonary allergic inflammation. Molecular studies indicate that IGF2BP2 switches M1 macrophages to M2 activation by targeting tuberous sclerosis 1 via an N6-methyladenosine (m6A)-dependent manner. Additionally, it is also shown a signal transducer and activators of transcription 6 (STAT6)-high mobility group AT-hook 2-IGF2BP2-peroxisome proliferator activated receptor-γ axis involves in M2 macrophages differentiation. These findings highlight a key role of IGF2BP2 in regulation of macrophages activation and imply a potential therapeutic target of macrophages in the inflammatory diseases.

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Dynamics of m6A RNA methylome during leukemogenesis reveals a role of IGF2BP2-PRMT6-MFSD2A signaling axis in maintaining AML stem cells [MeRIP-seq]

2023-06-20 | GSE210280 | GEO