ALKBH5 Demethylates the m6A Modification of SOCS3 in Microglia/Macrophages and Alleviates Neuroinflammation after Brain Injury
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PROVIDER: PRJNA1292149 | ENA |
REPOSITORIES: ENA
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Project description:Microglia/macrophage-induced neuroinflammation plays a crucial role in the progression of traumatic brain injury (TBI). However, the involvement of N6-methyladenosine (m6A) RNA modifications in this process remains elusive. Single-cell RNA sequencing (scRNA-seq) and m6A RNA immunoprecipitation sequencing (MeRIP-seq) across multiple time points post-injury revealed a strong correlation between m6A modifications and genes enriched in microglia/macrophage. Furthermore, the m6A demethylase ALKBH5 was identified as a key regulator of dynamic m6A patterns at the injury site. ALKBH5 suppression in microglia/macrophage exacerbated neuroinflammation in vitro and worsened neurological deficits in controlled cortical impact (CCI) models. MeRIP-qPCR and RNA pull-down assays revealed SOCS3 was a downstream target of ALKBH5-mediated m6A demethylation. This demethylation stabilized Socs3 mRNA and enhanced its protein expression, which in turn suppressed neuroinflammation via inhibiting the JAK2-STAT3 pathway. Conversely, SOCS3 depletion impaired functional recovery after injury. These findings unveiled a critical ALKBH5-m6A-SOCS3 regulatory axis that mitigated microglia/macrophage-driven neuroinflammation after TBI, underscoring its potential as a therapeutic intervention target for TBI progression.
2025-09-05 | GSE302863 | GEO
Project description:Microglia/macrophage_induced neuroinflammation plays a crucial role in the progression of traumatic brain injury (TBI). However, the involvement of N6_methyladenosine (m6A) RNA modifications in this process remains elusive. Single_cell RNA sequencing (scRNA_seq) and m6A RNA immunoprecipitation sequencing (MeRIP_seq) across multiple time points post_injury revealed a strong correlation between m6A modifications and genes enriched in microglia/macrophage. Furthermore, the m6A demethylase ALKBH5 was identified as a key regulator of dynamic m6A patterns at the injury site. ALKBH5 suppression in microglia/macrophage exacerbated neuroinflammation in vitro and worsened neurological deficits in controlled cortical impact (CCI) models. MeRIP_qPCR and RNA pull_down assays revealed SOCS3 was a downstream target of ALKBH5_mediated m6A demethylation. This demethylation stabilized Socs3 mRNA and enhanced its protein expression, which in turn suppressed neuroinflammation via inhibiting the JAK2_STAT3 pathway. Conversely, SOCS3 depletion impaired functional recovery after injury. These findings unveiled a critical ALKBH5_m6A_SOCS3 regulatory axis that mitigated microglia/macrophage_driven neuroinflammation after TBI, underscoring its potential as a therapeutic intervention target for TBI progression.
2025-09-05 | GSE302776 | GEO
Project description:ALKBH5 Demethylates the m6A Modification of SOCS3 in Microglia/Macrophages and Alleviates Neuroinflammation after Brain Injury [scRNA-seq]
| PRJNA1292715 | ENA
Project description:N6-methyladenosine (m6A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as a new mammalian demethylase that oxidatively removes the m6A modification in mRNA in vitro and inside cells. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1552 differentially expressed genes which cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. We show that Alkbh5-deficiency impacts the expression levels of some of these mRNAs, supporting the observed phenotype. The discovery of this new RNA demethylase strongly suggests that the reversible m6A modification plays fundamental and broad functions in mammalian cells. RNA-seq in two cell types
2013-02-15 | E-GEOD-40132 | biostudies-arrayexpress
Project description:N6-methyladenosine (m6A) modification is the most prevalent RNA epigenetic regulation in eukaryotic cells. Recent studies focused on the association between m6A and non-coding RNAs. The demethylase ALKBH5 acts as critical oncogenes or tumor suppressors through multiple mechanisms in various cancers. Here, we find that ALKBH5 is highly expressed in GC tissues and is associated with poor prognosis. ALKBH5 promoted the proliferation and metastasis both in vitro and in vivo. ALKBH5 was recruited by LINC00659, which removed m6A modifications of JAK1, leading to the upregulated expression of JAK1.Since ALKBH5 and LINC00659 have oncogenic role in gastric cancer (GC) progression with poor prognosis, ALKBH5-LINC00659/m6A/JAK1 axis can be new biological mechanisms behind GC development and future therapeutic opportunities.
2024-08-17 | GSE182544 | GEO
Project description:Reflux of bile acids and subsequent caudal-related homeobox 2 (CDX2) activation contribute to gastric intestinal metaplasia (IM), which is a precursor of gastric cancer. However, the underlying mechanism by which bile acids cause this is not entirely clear. Here we demonstrated that alkylation repair homolog protein 5 (ALKBH5), which is a major RNA N6-adenosine demethylase, was required for bile acid-induced gastric IM. Mechanistically, we revealed the N6-methyladenosine (m6A) modification profile in gastric IM for the first time and identified ZNF333 as a bona fide m6A target of ALKBH5. ALKBH5 was shown to demethylate ZNF333 mRNA, leading to enhanced ZNF333 expression by abolishing m6A-YTHDF2-dependent mRNA degradation. In addition, ALKBH5 activated CDX2 and downstream intestinal markers by targeting the ZNF333/CYLD axis and activating NF-κB signaling. Reciprocally, p65, which is the key transcription factor of the canonical NF-κB pathway, enhanced the transcription activity of ALKBH5 in the nucleus, thus forming a positive feed-forward circuit. In addition, ALKBH5 levels were positively correlated with ZNF333 and CDX2 in IM tissues, indicating a significant clinical relevance. Collectively, our findings suggest an m6A modification-associated positive feed-forward loop between ALKBH5 and NF-κB signaling is involved in the generation of the IM phenotype from gastric epithelial cells. Targeting the ALKBH5/ZNF333/CYLD/CDX2 axis might be a useful therapeutic strategy for gastric IM in patients with bile regurgitation.
2021-10-14 | GSE179185 | GEO
Project description:N6-methyladenosine (m6A) modification is the most prevalent RNA epigenetic regulation in eukaryotic cells. Recent studies focused on the association between m6A and non-coding RNAs. The demethylase ALKBH5 acts as critical oncogenes or tumor suppressors through multiple mechanisms in various cancers. Here, we find that ALKBH5 is highly expressed in GC tissues and is associated with poor prognosis. ALKBH5 promoted the proliferation and metastasis both in vitro and in vivo. ALKBH5 was recruited by LINC00659, which removed m6A modifications of JAK1, leading to the upregulated expression of JAK1.Since ALKBH5 and LINC00659 have oncogenic role in gastric cancer (GC) progression with poor prognosis, ALKBH5-LINC00659/m6A/JAK1 axis can be new biological mechanisms behind GC development and future therapeutic opportunities.
2024-08-17 | GSE182543 | GEO
Project description:N6-methyladenosine (m6A) modification is the most prevalent RNA epigenetic regulation in eukaryotic cells. Recent studies focused on the association between m6A and non-coding RNAs. The demethylase ALKBH5 acts as critical oncogenes or tumor suppressors through multiple mechanisms in various cancers. Here, we find that ALKBH5 is highly expressed in GC tissues and is associated with poor prognosis. ALKBH5 promoted the proliferation and metastasis both in vitro and in vivo. ALKBH5 was recruited by LINC00659, which removed m6A modifications of JAK1, leading to the upregulated expression of JAK1.Since ALKBH5 and LINC00659 have oncogenic role in gastric cancer (GC) progression with poor prognosis, ALKBH5-LINC00659/m6A/JAK1 axis can be new biological mechanisms behind GC development and future therapeutic opportunities.
2024-08-17 | GSE182542 | GEO
Project description:Abstract：Our previous study found that 1-nitropyrene (1-NP) exposure evoked pulmonary fibrosis in mice. However, the exact mechanism remained elusive. We found that 1-NP induced telomere damage and cellular senescence in mice lungs and MLE-12 cells. Further research showed that 1-NP downregulated telomere repeat binding factor 2 (TRF2), and upregulated FBXW7. Mechanistically, 1-NP-caused TRF2 ubiquitination and proteasomal degradation depended on E3 ubiquitin ligase activity of FBXW7. Moreover, 1-NP upregulated FBXW7 m6A modification via an ALKBH5-YTHDF1-dependent manner. Further analysis found 1-NP promoted ALKBH5 SUMOylation and subsequent proteasomal degradation. Additionally, 1-NP evoked mitochondrial reactive oxygen species (mtROS) overproduction. Mito-TEMPO, a mitochondrial-targeted antioxidant, mitigated 1-NP-caused mtROS overproduction, ALKBH5 SUMOylation, FBXW7 m6A modification, TRF2 degradation and cellular senescence. Taken together, mtROS-initiated ALKBH5 SUMOylation and subsequent FBXW7 m6A modification is indispensable in TRF2 degradation and cellular senescence in pulmonary epithelial cells during 1-NP-induced pulmonary fibrosis. Our study provides target intervention measures towards 1-NP-evoked pulmonary fibrosis.
2023-12-31 | GSE251659 | GEO
Project description:Abstract：Our previous study found that 1-nitropyrene (1-NP) exposure evoked pulmonary fibrosis in mice. However, the exact mechanism remained elusive. We found that 1-NP induced telomere damage and cellular senescence in mice lungs and MLE-12 cells. Further research showed that 1-NP downregulated telomere repeat binding factor 2 (TRF2), and upregulated FBXW7. Mechanistically, 1-NP-caused TRF2 ubiquitination and proteasomal degradation depended on E3 ubiquitin ligase activity of FBXW7. Moreover, 1-NP upregulated FBXW7 m6A modification via an ALKBH5-YTHDF1-dependent manner. Further analysis found 1-NP promoted ALKBH5 SUMOylation and subsequent proteasomal degradation. Additionally, 1-NP evoked mitochondrial reactive oxygen species (mtROS) overproduction. Mito-TEMPO, a mitochondrial-targeted antioxidant, mitigated 1-NP-caused mtROS overproduction, ALKBH5 SUMOylation, FBXW7 m6A modification, TRF2 degradation and cellular senescence. Taken together, mtROS-initiated ALKBH5 SUMOylation and subsequent FBXW7 m6A modification is indispensable in TRF2 degradation and cellular senescence in pulmonary epithelial cells during 1-NP-induced pulmonary fibrosis. Our study provides target intervention measures towards 1-NP-evoked pulmonary fibrosis.
2023-12-31 | GSE251884 | GEO