Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China; Liangzhu Laboratory, Zhejiang University, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang 311121, China; The State Key Laboratory for Complex, Severe, and Rare Diseases, Haihe Laboratory of Cell Ecosystem, Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China; Liangzhu Laboratory, Zhejiang University, Hangzhou, Zhejiang 311121, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang 311121, China.
J Genet Genomics. 2024 Jun;51(6):594-607. doi: 10.1016/j.jgg.2024.02.003. Epub 2024 Feb 24.
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.
mRNA 的转录后调控是基因表达的一个关键组成部分。该过程的破坏对正常发育有不利影响，并导致各种疾病。寻找新型的转录后调控因子并探索其作用对于理解发育和疾病至关重要。通过对红细胞特征全基因组关联研究（GWAS）和红细胞生成转录组的多模态分析，我们确定 FAM46C，一种非典型的 RNA 多聚（A）聚合酶，是红细胞正常发育所必需的因素。FAM46C 在红细胞谱系的晚期高度表达，其发育上调受红细胞特异性增强子控制。我们证明 FAM46C 以依赖聚合酶活性的方式稳定 mRNA 并调节红细胞分化。此外，我们鉴定了溶酶体和线粒体成分的转录本作为 FAM46C 的高度可信的体内靶标，这与成熟红细胞对细胞器的大量清除和细胞氧化还原稳态的维持的需求一致。总之，我们的研究揭示了 FAM46C 在正向调节溶酶体和线粒体成分方面的独特作用，从而促进了红细胞生成。
