RESUMO
The post-transcriptional regulation of mRNA is a crucial component of gene expression. The disruption of this process has detrimental effects on the normal development and gives rise to various diseases. Searching for novel post-transcriptional regulators and exploring their roles are essential for understanding development and disease. Through a multimodal analysis of red blood cell trait genome-wide association studies (GWAS) and transcriptomes of erythropoiesis, we identify FAM46C, a non-canonical RNA poly(A) polymerase, as a necessary factor for proper red blood cell development. FAM46C is highly expressed in the late stages of the erythroid lineage, and its developmental upregulation is controlled by an erythroid-specific enhancer. We demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent manner. Furthermore, we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C, which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox homeostasis. In conclusion, our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components, thereby promoting erythropoiesis.
Assuntos
Eritropoese , Polinucleotídeo Adenililtransferase , Eritropoese/genética , Humanos , Animais , Camundongos , Polinucleotídeo Adenililtransferase/genética , Polinucleotídeo Adenililtransferase/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Estudo de Associação Genômica Ampla , Mitocôndrias/genética , Mitocôndrias/metabolismo , Diferenciação Celular/genética , Lisossomos/metabolismo , Lisossomos/genética , Eritrócitos/metabolismo , Transcriptoma/genéticaRESUMO
BACKGROUND: Gout is a common and debilitating condition that is associated with significant morbidity and mortality. Despite advances in medical treatment, the global burden of gout continues to increase, particularly in high-sociodemographic index (SDI) regions. OBJECTIVE: To address the aforementioned issue, we used age-period-cohort (APC) modeling to analyze global trends in gout incidence and prevalence from 1990 to 2019. METHODS: Data were extracted from the Global Burden of Disease Study 2019 to assess all-age prevalence and age-standardized prevalence rates, as well as years lived with disability rates, for 204 countries and territories. APC effects were also examined in relation to gout prevalence. Future burden prediction was carried out using the Nordpred APC prediction of future incidence cases and the Bayesian APC model. RESULTS: The global gout incidence has increased by 63.44% over the past 2 decades, with a corresponding increase of 51.12% in global years lived with disability. The sex ratio remained consistent at 3:1 (male to female), but the global gout incidence increased in both sexes over time. Notably, the prevalence and incidence of gout were the highest in high-SDI regions (95% uncertainty interval 14.19-20.62), with a growth rate of 94.3%. Gout prevalence increases steadily with age, and the prevalence increases rapidly in high-SDI quantiles for the period effect. Finally, the cohort effect showed that gout prevalence increases steadily, with the risk of morbidity increasing in younger birth cohorts. The prediction model suggests that the gout incidence rate will continue to increase globally. CONCLUSIONS: Our study provides important insights into the global burden of gout and highlights the need for effective management and prophylaxis of this condition. The APC model used in our analysis provides a novel approach to understanding the complex trends in gout prevalence and incidence, and our findings can inform the development of targeted interventions to address this growing health issue.
