Blood cell formation is classically thought to occur through a hierarchical differentiation process, although recent studies have shown that lineage commitment may occur earlier in hematopoietic stem and progenitor cells (HSPCs). The relevance to human blood diseases and the underlying regulation of these refined models remain poorly understood. By studying a genetic blood disorder, Diamond-Blackfan anemia (DBA), where the majority of mutations affect ribosomal proteins and the erythroid lineage is selectively perturbed, we are able to gain mechanistic insight into how lineage commitment is programmed normally and disrupted in disease. We show that in DBA, the pool of available ribosomes is limited, while ribosome composition remains constant. Surprisingly, this global reduction in ribosome levels more profoundly alters translation of a select subset of transcripts. We show how the reduced translation of select transcripts in HSPCs can impair erythroid lineage commitment, illuminating a regulatory role for ribosome levels in cellular differentiation.

中文翻译：

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核糖体水平选择性调节人类造血的翻译和沿袭承诺。

尽管最近的研究表明血统形成可能在造血干细胞和祖细胞（HSPC）中发生得较早，但通常认为血细胞形成是通过分级分化过程发生的。与人类血液疾病的相关性以及这些精炼模型的基本调控仍知之甚少。通过研究遗传性血液疾病，即钻石-布莱克范贫血（DBA），其中大多数突变会影响核糖体蛋白，并且选择性干扰红系谱系，我们能够获得有关谱系承诺正常编程和疾病破坏机制的机械学见识。我们表明，在DBA中，可用核糖体的库是有限的，而核糖体的组成则保持不变。出奇，核糖体水平的这种总体降低更深刻地改变了所选转录本子集的翻译。我们显示如何减少HSPCs中的特定转录物的翻译会损害类红系谱系承诺，阐明核糖体水平在细胞分化中的调控作用。