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Hypoxia causes a series of responses supporting cells to survive in harsh environments. Substantial post-transcriptional and translational regulation during hypoxia has been observed. However, detailed regulatory mechanism in response to hypoxia is still far from complete. RNA m6A modification has been proven to govern the life cycle of RNAs. Here, we reported that total m6A level of mRNAs was decreased during hypoxia, which might be mediated by the induction of m6A eraser, ALKBH5. Meanwhile, expression levels of most YTH family members of m6A readers were systematically down-regulated. Transcriptome-wide analysis of m6A revealed a drastic reprogramming of m6A epitranscriptome during cellular hypoxia. Integration of m6A epitranscriptome with either RNA-seq based transcriptome analysis or mass spectrometry (LC-MS/MS) based proteome analysis of cells upon hypoxic stress revealed that reprogramming of m6A epitranscriptome reshaped the transcriptome and proteome, thereby supporting efficient generation of energy for adaption to hypoxia. Moreover, ATP production was blocked when silencing an m6A eraser, ALKBH5, under hypoxic condition, demonstrating that m6A pathway is an important regulator during hypoxic response. Collectively, our studies indicate that crosstalk between m6A and HIF1 pathway is essential for cellular response to hypoxia, providing insights into the underlying molecular mechanisms during hypoxia.

Objective: This study aimed to explore the link between dietary vitamin C intake and hyperuricemia/gout, utilizing Mendelian randomization to assess causality. Methods: We analyzed cross‐sectional data from the National Health and Nutrition Examination Survey (2007–2018) to investigate the association. Mendelian randomization studies, using genetic data from genome‐wide association surveys, were conducted to infer causality between vitamin C intake and hyperuricemia/gout. The weighted logistic regression analysis and the instrumental variable based on the inverse‐variance weighting served as the primary analytical tool, with sensitivity analyses to ensure robustness. Results: After adjusting for covariates, a stable association was observed between vitamin C intake and hyperuricemia/gout risk. Those consuming >111.75 mg of vitamin C generally had a lower risk. Vitamin C intake recommendations of 75–525 mg and 75–225 mg appeared effective for hyperuricemia and gout, respectively. Mendelian randomization analysis revealed a negative association between vitamin C intake and hyperuricemia (OR = 0.985, 95% CI = 0.973–0.997, p =.015) and gout (OR = 0.857, 95% CI = 0.797–0.921, p <.001). Reverse Mendelian randomization indicated no reverse causality. Conclusion: We hypothesize that a dietary vitamin C intake of 75–525 mg or 75–225 mg may reduce the risk of hyperuricemia and gout, respectively. Further research with larger samples is required to confirm this. [ABSTRACT FROM AUTHOR]

Hypoxia causes a series of responses supporting cells to survive in harsh environments. Substantial post-transcriptional and translational regulation during hypoxia has been observed. However, detailed regulatory mechanism in response to hypoxia is still far from complete. RNA m6A modification has been proven to govern the life cycle of RNAs. Here, we reported that total m6A level of mRNAs was decreased during hypoxia, which might be mediated by the induction of m6A eraser, ALKBH5. Meanwhile, expression levels of most YTH family members of m6A readers were systematically down-regulated. Transcriptome-wide analysis of m6A revealed a drastic reprogramming of m6A epitranscriptome during cellular hypoxia. Integration of m6A epitranscriptome with either RNA-seq based transcriptome analysis or mass spectrometry (LC-MS/MS) based proteome analysis of cells upon hypoxic stress revealed that reprogramming of m6A epitranscriptome reshaped the transcriptome and proteome, thereby supporting efficient generation of energy for adaption to hypoxia. Moreover, ATP production was blocked when silencing an m6A eraser, ALKBH5, under hypoxic condition, demonstrating that m6A pathway is an important regulator during hypoxic response. Collectively, our studies indicate that crosstalk between m6A and HIF1 pathway is essential for cellular response to hypoxia, providing insights into the underlying molecular mechanisms during hypoxia. [ABSTRACT FROM AUTHOR]

Hypoxia causes a series of responses supporting cells to survive in harsh environments. Substantial post-transcriptional and translational regulation during hypoxia has been observed. However, detailed regulatory mechanism in response to hypoxia is still far from complete. RNA m 6 A modification has been proven to govern the life cycle of RNAs. Here, we reported that total m 6 A level of mRNAs was decreased during hypoxia, which might be mediated by the induction of m 6 A eraser, ALKBH5. Meanwhile, expression levels of most YTH family members of m 6 A readers were systematically down-regulated. Transcriptome-wide analysis of m 6 A revealed a drastic reprogramming of m 6 A epitranscriptome during cellular hypoxia. Integration of m 6 A epitranscriptome with either RNA-seq based transcriptome analysis or mass spectrometry (LC-MS/MS) based proteome analysis of cells upon hypoxic stress revealed that reprogramming of m 6 A epitranscriptome reshaped the transcriptome and proteome, thereby supporting efficient generation of energy for adaption to hypoxia. Moreover, ATP production was blocked when silencing an m 6 A eraser, ALKBH5, under hypoxic condition, demonstrating that m 6 A pathway is an important regulator during hypoxic response. Collectively, our studies indicate that crosstalk between m 6 A and HIF1 pathway is essential for cellular response to hypoxia, providing insights into the underlying molecular mechanisms during hypoxia.