Fine‐Tuning of Cholesterol Homeostasis Controls Erythroid Differentiation

Advanced Science

Junjie Chen¹  Qi Sun²  Jian Li²  Ruihao Zhang²  Lixia Huang²  Yi Lu²  Yanxia Li³  Baobing Zhao³  Zhiyuan Lu³  Yuemao Shen³  Yan Xu³  Qian Zhou³ 

[1] Analysis and Measurement Center School of Pharmaceutical Sciences Xiamen University Xiamen Fujian 361001 China;Department of Biochemistry and Molecular Biology School of Basic Medical Sciences Cheeloo College of Medicine Shandong University Jinan Shandong 250012 China;Key Laboratory of Chemical Biology (Ministry of Education) School of Pharmaceutical Sciences Cheeloo College of Medicine Shandong University Jinan Shandong 250012 China;

关键词: cholesterol homeostasis;    enucleation;    erythropoiesis;    GATA1;    ribosome biogenesis;    SREBP2;   

DOI  :  10.1002/advs.202102669

来源: DOAJ

【 摘 要 】

Abstract Lipid metabolism is essential for stemness maintenance, self‐renewal, and differentiation of stem cells, however, the regulatory function of cholesterol metabolism in erythroid differentiation is poorly studied. In the present study, a critical role for cholesterol homeostasis in terminal erythropoiesis is uncovered. The master transcriptional factor GATA1 binds to Sterol‐regulatory element binding protein 2 (SREBP2) to downregulate cholesterol biosynthesis, leading to a gradual reduction in intracellular cholesterol levels. It is further shown that reduced cholesterol functions to block erythroid proliferation via the cholesterol/mTORC1/ribosome biogenesis axis, which coordinates cell cycle exit in the late stages of erythroid differentiation. The interaction of GATA1 and SREBP2 also provides a feedback loop for regulating globin expression through the transcriptional control of NFE2 by SREBP2. Importantly, it is shown that disrupting intracellular cholesterol hemostasis resulted in defect of terminal erythroid differentiation in vivo. These findings demonstrate that fine‐tuning of cholesterol homeostasis emerges as a key mechanism for regulating erythropoiesis.

【 授权许可】

Unknown