Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis.
Ribosome Levels Selectively Regulate Translation and Lineage Commitment in Human Hematopoiesis.
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DOI：
10.1016/j.cell.2018.02.036
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发表时间：
2018-03-22
期刊：
影响因子：
64.5
通讯作者：
Sankaran VG
中科院分区：
文献类型：
--
作者：
Khajuria RK;Munschauer M;Ulirsch JC;Fiorini C;Ludwig LS;McFarland SK;Abdulhay NJ;Specht H;Keshishian H;Mani DR;Jovanovic M;Ellis SR;Fulco CP;Engreitz JM;Schütz S;Lian J;Gripp KW;Weinberg OK;Pinkus GS;Gehrke L;Regev A;Lander ES;Gazda HT;Lee WY;Panse VG;Carr SA;Sankaran VG
传统上认为，血细胞的形成是通过等级分化过程发生的，尽管最近的研究表明，谱系承诺可能在造血干细胞和祖细胞（HSPCs）中更早发生。与人类血液疾病的相关性和这些改进模型的潜在调节仍然知之甚少。通过研究一种遗传性血液疾病，Diamond-Blackfan贫血（DBA），其中大多数突变影响核糖体蛋白，红系谱系被选择性地扰乱，我们能够获得关于谱系承诺如何正常编程和疾病中中断的机制见解。我们表明，在DBA中，可用的核糖体池是有限的，而核糖体组成保持不变。令人惊讶的是，这种核糖体水平的整体降低更深刻地改变了转录本的一个选择子集的翻译。我们展示了HSPCs中选择转录本的翻译减少如何损害红系谱系承诺，阐明了核糖体水平在细胞分化中的调节作用。Diamond-Blackfan贫血中核糖体水平的全球降低深刻地改变了转录本的一个选择子集的翻译，从而阻碍了红系谱系的承诺。
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. A global reduction in ribosome levels in Diamond-Blackfan anemia profoundly alters translation of a select subset of transcripts thereby impeding erythroid lineage commitment.
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影响因子：
64.5
作者：
Buszczak M;Signer RA;Morrison SJ
通讯作者：
Morrison SJ
影响因子：
8.8
作者：
Capellera-Garcia S;Pulecio J;Dhulipala K;Siva K;Rayon-Estrada V;Singbrant S;Sommarin MN;Walkley CR;Soneji S;Karlsson G;Raya Á;Sankaran VG;Flygare J
通讯作者：
Flygare J
影响因子：
64.5
作者：
Kim AR;Ulirsch JC;Wilmes S;Unal E;Moraga I;Karakukcu M;Yuan D;Kazerounian S;Abdulhay NJ;King DS;Gupta N;Gabriel SB;Lander ES;Patiroglu T;Ozcan A;Ozdemir MA;Garcia KC;Piehler J;Gazda HT;Klein DE;Sankaran VG
通讯作者：
Sankaran VG
影响因子：
7.3
作者：
Henras, Anthony K.;Plisson-Chastang, Celia;O'Donohue, Marie-Francoise;Chakraborty, Anirban;Gleizes, Pierre-Emmanuel
通讯作者：
Gleizes, Pierre-Emmanuel
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM