Liu Xiuli, Gogate Aishwarya A, Tastemel Melodi, Malladi Venkat S, Yao Huiyu, Nguyen Kim, Huang Lily Jun-Shen, Bai Xiaoying
Laboratory of Molecular Genetics of Blood Development, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Reproductive Biology Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Blood Adv. 2017 Aug 8;1(18):1358-1367. doi: 10.1182/bloodadvances.2017008383.
The NELF complex is a metazoan-specific factor essential for establishing transcription pausing. Although NELF has been implicated in cell fate regulation, the cellular regulation of NELF and its intrinsic role in specific lineage differentiation remains largely unknown. Using mammalian hematopoietic differentiation as a model system, here we identified a dynamic change of NELF-mediated transcription pausing as a novel mechanism regulating hematopoietic differentiation. We found a sharp decrease of NELF protein abundance upon granulocytic differentiation and a subsequent genome-wide reduction of transcription pausing. This loss of pausing coincides with activation of granulocyte-affiliated genes and diminished expression of progenitor markers. Functional studies revealed that sustained expression of NELF inhibits granulocytic differentiation, whereas NELF depletion in progenitor cells leads to premature differentiation towards the granulocytic lineage. Our results thus uncover a previously unrecognized regulation of transcription pausing by modulating NELF protein abundance to control cellular differentiation.
NELF复合物是后生动物特有的一种因子，对于建立转录暂停至关重要。尽管NELF已被认为与细胞命运调控有关，但其细胞调控以及在特定谱系分化中的内在作用仍基本未知。以哺乳动物造血分化作为模型系统，我们在此鉴定出NELF介导的转录暂停的动态变化是一种调节造血分化的新机制。我们发现粒细胞分化时NELF蛋白丰度急剧下降，随后全基因组范围的转录暂停减少。这种暂停的丧失与粒细胞相关基因的激活以及祖细胞标志物表达的减少相吻合。功能研究表明，持续表达NELF会抑制粒细胞分化，而祖细胞中NELF的缺失会导致过早向粒细胞谱系分化。因此，我们的结果揭示了一种此前未被认识到的通过调节NELF蛋白丰度来控制细胞分化的转录暂停调控机制。
