The non-canonical poly(A) polymerase FAM46C promotes erythropoiesis [RNA-seq]

Posttranscriptional regulation of mRNA is a crucial component of gene expression. The disruption of this process can have detrimental effects on normal development and give rise to various diseases. The search for novel posttranscriptional regulators and the exploration of their roles are essential for understanding development and disease. Through a multimodal analysis of red blood cell trait GWASs and transcriptomes of erythropoiesis, we identified FAM46C, a non-canonical RNA poly(A) polymerase, as a necessary factor for proper red blood cell development. FAM46C is highly expressed in late stages of the erythroid lineage, and its developmental upregulation is controlled by an erythroid-specific enhancer. We demonstrate that FAM46C stabilizes mRNA in an enzyme activity dependent manner by maintaining the poly(A) tails of its targets. Furthermore, we identified 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 novel role of FAM46C in positively regulating the level of lysosome and mitochondria components, thereby promoting erythropoiesis. RNA-seq for FAM46C knockdown, knockout clonal and overxpression in HUDEP-2 cells.

mRNA的转录后调控是基因表达的关键组成部分。该过程的紊乱会对正常发育产生不利影响，并引发多种疾病。探寻新型转录后调控因子并解析其功能，对于阐明发育与疾病的机制至关重要。本研究通过对红细胞性状全基因组关联研究（Genome-Wide Association Study, GWAS）与红细胞生成转录组开展多组学联合分析，鉴定出非经典RNA聚(A)聚合酶（poly(A) polymerase）FAM46C是正常红细胞发育所必需的因子。FAM46C在红系谱系的晚期阶段高表达，其发育性上调受红系特异性增强子调控。本研究证实，FAM46C可通过维持靶标mRNA的聚(A)尾长度，以依赖其酶活性的方式稳定靶标mRNA。此外，本研究鉴定出溶酶体与线粒体组分相关转录本为FAM46C的高可信度体内靶标，这与成熟红细胞需大量清除细胞器并维持细胞氧化还原稳态的需求相符。综上，本研究揭示了FAM46C的全新功能：它可正向调控溶酶体与线粒体组分的表达水平，进而促进红细胞生成。本研究对HUDEP-2细胞中FAM46C的敲低、克隆敲除及过表达样本进行了RNA测序。