RNA polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation
RNA polymerase II pausing temporally coordinates cell cycle progression and erythroid differentiation
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DOI：
10.1016/j.devcel.2023.07.018
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发表时间：
2023-10-23
影响因子：
11.8
通讯作者：
Churchman，L. Stirling
中科院分区：
文献类型：
--
作者：
Martell，Danya J.;Merens，Hope E.;Churchman，L. Stirling
启动子-近端暂停RNA聚合酶II （RNA Pol II）的控制释放对基因调控至关重要。然而，研究RNA Pol II暂停是具有挑战性的，因为暂停释放因子几乎都是必不可少的。在这项研究中，我们在β-地中海贫血患者中发现了编码SPT5基因的supt5h的杂合功能缺失突变。在健康人类细胞的红细胞生成过程中，细胞周期基因在细胞从祖细胞向前体细胞转变过程中高度暂停。当致病突变被supt5heiting重现时，RNA Pol II暂停释放被全局破坏，当细胞开始从祖细胞向前体转变时，分化被延迟，伴随着红细胞特异性基因表达和细胞周期动力学的短暂滞后。尽管这种延迟，细胞最终分化，细胞周期期分布正常化。因此，在红细胞生成过程的关键过渡阶段，阻碍暂停释放会干扰增殖和分化动力学，从而确定RNA Pol II暂停在暂时协调细胞周期和红细胞分化中的作用。
Controlled release of promoter-proximal paused RNA polymerase II (RNA Pol II) is crucial for gene regulation. However, studying RNA Pol II pausing is challenging, as pause-release factors are almost all essential. In this study, we identified heterozygous loss-of-function mutations inSUPT5H, which encodes SPT5, in individuals with β-thalassemia. During erythropoiesis in healthy human cells, cell cycle genes were highly paused as cells transition from progenitors to precursors. When the pathogenic mutations were recapitulated bySUPT5Hediting, RNA Pol II pause release was globally disrupted, and as cells began transitioning from progenitors to precursors, differentiation was delayed, accompanied by a transient lag in erythroid-specific gene expression and cell cycle kinetics. Despite this delay, cells terminally differentiate, and cell cycle phase distributions normalize. Therefore, hindering pause release perturbs proliferation and differentiation dynamics at a key transition during erythropoiesis, identifying a role for RNA Pol II pausing in temporally coordinating the cell cycle and erythroid differentiation.