Acute exposure to MK-801, the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, induces schizophrenia-like behavioural changes in juvenile male mice. However, the effects of acute MK-801 exposure on brain gene expression at the translation level remain unclear. Here, we conducted ribosome profiling analysis on the prefrontal cortex (PFC) of acute MK-801-exposed juvenile male mice. We found 357 differentially translated genes, with the N⁴-acetylcytidine (ac⁴C) consensus motif enriched in the transcripts with increased translation efficiency. Acetylated RNA immunoprecipitation sequencing revealed 148 differentially acetylated peaks, of which 121 were hyperacetylated, and 27 were hypoacetylated. Genes harbouring these peaks were enriched in pathways related to axon guidance, Hedgehog signalling pathway, neuron differentiation, and memory. Grin2a encodes an NMDA receptor subunit NMDAR2A, and its human orthologue is a strong susceptibility gene for schizophrenia. Grin2a mRNA was hyperacetylated and exhibited significantly increased translation efficiency. NMDAR2A protein level was increased in MK-801-exposed PFC. Pretreatment of Remodelin, an inhibitor of N-acetyltransferase 10, returned the NMDAR2A protein levels to normal and partially reversed schizophrenia-like behaviours of MK-801-exposed mice, shedding light on the possible role of mRNA acetylation in the aetiology of schizophrenia.

01 Nov 2024·Molecular Metabolism

Improvement of MASLD and MASH by suppression of hepatic N-acetyltransferase 10

Article

Author: Ma, Xiaojing ; Lu, Jie ; Luo, Yunchen ; Liu, Yuejun ; Zhang, Ni ; Yang, Yanying ; Zheng, Ming-Hua ; Hu, Cheng ; Dong, Zhixia ; Lu, Yan ; Ma, Mingyue ; Ruan, Cheng-Chao ; Wan, Xinjian ; Zhang, Shuo ; Zhou, Bing

OBJECTIVEMetabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA. N-acetyltransferase 10 (NAT10) has not been fully explored in MASLD and MASH.METHODSThe clinical relevance of NAT10 was evaluated based on its expression in various mouse and human models of MASLD and MASH. Acetylated RNA immunoprecipitation sequencing and mRNA stability assays were used to explore the role of NAT10 in regulating ac4C modification and expression of target genes. Genetically engineered mice were employed to investigate the role of NAT10 in MASLD and MASH progression.RESULTSHepatic NAT10 expression was significantly increased in multiple mice and humans of MASLD and MASH. Genetic knockout of NAT10 protected mice from diet-induced hepatic steatosis and steatohepatitis, whereas overexpression of NAT10 exacerbated high-fat-diet-induced liver steatosis. Mechanistically, NAT10 binds to Srebp-1c mRNA, promoting its stability and expression, thereby upregulating lipogenic enzymes. Treatment with Remodelin, a NAT10-specific inhibitor, effectively ameliorates liver steatosis and dyslipidemia in a preclinical mouse model.CONCLUSIONSOur findings indicate that NAT10 could regulate lipid metabolism in MASLD and MASH by stabilizing Srebp-1c mRNA and upregulating lipogenic enzymes. This study highlights the role of NAT10 and RNA acetylation in the pathogenesis of MASLD and MASH. Thus, our findings suggest a promising new therapeutic approach, such as the use of NAT10 inhibitor, for treating metabolic liver disease.

01 Jul 2024·Journal of Advanced Research

NAT10 promotes osteoclastogenesis in inflammatory bone loss by catalyzing Fos mRNA ac4C modification and upregulating MAPK signaling pathway

Article

Author: Yang, Ruhan ; Lin, Lu ; Gu, Yuting ; Cui, Zhurong ; Li, Guanglong ; Lu, Eryi ; Yu, Weijun ; Tang, Jiaqi ; Jin, Min

INTRODUCTIONExcessive osteoclastogenesis is a key driver of inflammatory bone loss. Suppressing osteoclastogenesis has always been considered essential for the treatment of inflammatory bone loss. N-acetyltransferase 10 (NAT10) is the sole enzyme responsible for N4-acetylcytidine (ac4C) modification of mRNA, and is involved in cell development. However, its role in osteoclastogenesis and inflammatory bone loss remained elusive.OBJECTIVESWe aimed to clarify the regulatory mechanism of NAT10 and ac4C modification in osteoclastogenesis and inflammatory bone loss.METHODSNAT10 expression and ac4C modification during osteoclastogenesis were determined by quantitative real-time PCR (qPCR), western blotting, dot blot and immunofluorescent staining, and the effect of NAT10 inhibition on osteoclast differentiation in vitro was measured by the tartrate-resistant acid phosphatase staining, podosome belts staining assay and bone resorption pit assay. Then, acRIP-qPCR and NAT10RIP-qPCR, ac4C site prediction, mRNA decay assay and luciferase reporter assay were performed to further study the underlying mechanisms. At last, mice models of inflammatory bone loss were applied to verify the therapeutic effect of NAT10 inhibition in vivo.RESULTSNAT10 expression was upregulated during osteoclast differentiation and highly expressed in alveolar bone osteoclasts from periodontitis mice. Inhibition of NAT10 notably reduced osteoclast differentiation in vitro, as indicated by great reduction of tartrated resistant acid phosphatse positive multinuclear cells, osteoclast-specific gene expression, F-actin ring formation and bone resorption capacity. Mechanistically, NAT10 catalyzed ac4C modification of Fos (encoding AP-1 component c-Fos) mRNA and maintained its stabilization. Besides, NAT10 promoted MAPK signaling pathway and thereby activated AP-1 (c-Fos/c-Jun) transcription for osteoclastogenesis. Therapeutically, administration of Remodelin, the specific inhibitor of NAT10, remarkably impeded the ligature-induced alveolar bone loss and lipopolysaccharide-induced inflammatory calvarial osteolysis.CONCLUSIONSOur study demonstrated that NAT10-mediated ac4C modification is an important epigenetic regulation of osteoclast differentiation and proposed a promising therapeutic target for inflammatory bone loss.

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Indication	Highest Phase	Country/Location	Organization	Date
Hutchinson-Gilford progeria syndrome	Preclinical	GB	University of Cambridge	02 May 2014

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