Dataset Information

ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m⁶A modification-mediated RNA stability control.

ABSTRACT: N⁶-methyladenosine (m⁶A) RNA modification controls numerous cellular processes. To what extent these post-transcriptional regulatory mechanisms play a role in hematopoiesis has not been fully elucidated. We here show that the m⁶A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m⁶A-dependent manner. Loss of ALKBH5 results in increased RNA methylation and instability of oxoglutarate-dehydrogenase (Ogdh) messenger RNA and reduction of OGDH protein levels. Limited OGDH availability slows the tricarboxylic acid (TCA) cycle with accumulation of α-ketoglutarate (α-KG) and conversion of α-KG into L-2-hydroxyglutarate (L-2-HG). L-2-HG inhibits energy production in both murine and human hematopoietic cells in vitro. Impaired mitochondrial energy production confers competitive disadvantage to HSPCs and limits clonogenicity of Mll-AF9-induced leukemia. Our study uncovers a mechanism whereby the RNA m⁶A demethylase ALKBH5 regulates the stability of metabolic enzyme transcripts, thereby controlling energy metabolism in hematopoiesis and leukemia.

SUBMITTER: Gao Y

PROVIDER: S-EPMC10636609 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control.

Gao Yimeng Y Zimmer Joshua T JT Vasic Radovan R Liu Chengyang C Gbyli Rana R Zheng Shu-Jian SJ Patel Amisha A Liu Wei W Qi Zhihong Z Li Yaping Y Nelakanti Raman R Song Yuanbin Y Biancon Giulia G Xiao Andrew Z AZ Slavoff Sarah S Kibbey Richard G RG Flavell Richard A RA Simon Matthew D MD Tebaldi Toma T Li Hua-Bing HB Halene Stephanie S

Cell reports 20230923 10

N6-methyladenosine (m6A) RNA modification controls numerous cellular processes. To what extent these post-transcriptional regulatory mechanisms play a role in hematopoiesis has not been fully elucidated. We here show that the m6A demethylase alkB homolog 5 (ALKBH5) controls mitochondrial ATP production and modulates hematopoietic stem and progenitor cell (HSPC) fitness in an m6A-dependent manner. Loss of ALKBH5 results in increased RNA methylation and ...[more]

PMID: 37742191

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Project description:BackgroundTo investigate the role of microglia polarization in the pathogenesis of diabetic retinopathy, and study the mechanism of ALKBH5-mediated m6A modification of A20 of retinal microglia polarization.MethodsDiabetics rats were constructed and the M1/M2 polarization of retinal microglia was determined using immunofluorescence, flow cytometry, and quantitative real-time PCR (qRT-PCR). Glucose at different concentrations was added to treat the microglia, and the polarization rate was detected. RNA sequencing was performed to identify the differentially expressed gene in glucose treated microglia, and A20 expression was confirmed by qRT-PCR and western blotting. Lentiviruses encoding shRNA for A20 or overexpressing A20 were constructed to clarify the role of A20 in microglia polarization in vitro and vivo. N6-methyladenosine (m6A) modification level and degradation rate of A20 were determined and m6A related proteins were detected.ResultsDiabetics rats showed a higher M1 polarization rate but lower M2 polarization rate of retinal microglia. With the increase of glucose concentration, microglia tend to polarize into M1 inflammatory type rather than M2 anti-inflammatory type. Shown by RNA sequencing, glucose treated microglia showed a differentially expressed gene profile, which was enriched in kinds of inflammatory categories and pathways. A20 expression was lower in microglia with glucose treatment, which was demonstrated to negatively regulate the M1 polarization. Moreover, intraocular injection of A20-overexpression lentiviruses (OE-A20) rectified the enhanced M1 retinal microglia polarization of diabetes rats. The higher m6A modification level and faster degradation rate of A20 was observed in glucose treated microglia, which was mediated by m6A demethylase ALKBH5.ConclusionLower expression A20 resulted in the enhanced M1 polarization of retinal microglia in diabetic retinopathy, which was caused by ALKBH5 mediated m6A modification. This study may provide new perspectives on not only the pathogenesis but also the diagnosis and treatment for diabetic retinopathy.

Dataset Information

ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m⁶A modification-mediated RNA stability control.

Publications

ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m<sup>6</sup>A modification-mediated RNA stability control.

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