RNA-seq transcriptional profiling in human primary fetal and adult CD34+ hematopoietic stem/progenitor cells (HSPCs) erythroid progenitor cells (ProEs)

Advances in sequencing-based genomic profiling present a new challenge of explaining how changes in DNA/RNA are translated into proteins linking genotypes to phenotypes. The developing erythroid cells require highly coordinated gene expression and metabolism, and serve as a unique model in dissecting regulatory events in development and disease. Here we compare the proteomic and transcriptomic changes in human hematopoietic stem/progenitor cells and lineage-committed erythroid progenitors, and uncover pathways related to mitochondrial biogenesis enhanced through post-transcriptional regulation. Two principal mitochondrial factors TFAM and PHB2 are tightly regulated at the protein level and indispensable for mitochondria and erythropoiesis. mTORC1 signaling is progressively enhanced to promote translation of mitochondrial proteins during erythroid specification. Genetic and pharmacological perturbation of mTORC1 or mitochondria impairs erythropoiesis. Our studies suggest a new mechanism for regulation of mitochondrial biogenesis through mTORC1-mediated protein translation, and may have direct relevance to the hematological defects associated with mitochondrial diseases and aging.

基于测序的基因组分析技术的进步，带来了一项新的研究挑战：阐释DNA/RNA的改变如何被翻译为蛋白质，进而连接基因型与表型。发育中的红细胞系细胞需要高度协同的基因表达与代谢过程，可作为解析发育与疾病中调控事件的独特模型。本研究对人类造血干/祖细胞以及谱系定向红系祖细胞中的蛋白质组与转录组变化进行比较，揭示了通过转录后调控增强的线粒体生物发生相关通路。两种主要的线粒体因子TFAM与PHB2在蛋白质水平受到严格调控，且对线粒体功能与红细胞生成不可或缺。在红系细胞特化过程中，哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）信号通路逐步被激活，以促进线粒体蛋白质的翻译。对mTORC1或线粒体进行遗传与药理学扰动，均会损害红细胞生成过程。本研究揭示了一种通过mTORC1介导的蛋白质翻译调控线粒体生物发生的新机制，该机制或与线粒体疾病及衰老相关的血液系统缺陷存在直接关联。