Activating transcription factor 3 coordinates differentiation of cardiac and hematopoietic progenitors by regulating glucose metabolism
Activating transcription factor 3 coordinates differentiation of cardiac and hematopoietic progenitors by regulating glucose metabolism
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激活转录因子 3 通过调节葡萄糖代谢协调心脏和造血祖细胞的分化
DOI：
10.1126/sciadv.aay9466
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发表时间：
2020
期刊：
影响因子：
13.6
通讯作者：
Zhou Yong
中科院分区：
文献类型：
--
作者：
Yin Hui-Min;Yan Li-Feng;Liu Qian;Peng Zheng;Zhang Chi-Yuan;Xia Yu;Su Dan;Gu Ai-Hua;Zhou Yong
ATF3为心脏和造血祖细胞提供代谢适应能力，以保护分化潜能。中胚层中的心脏和造血祖细胞(分别为CPS和HPS)最终形成一个组织良好的循环系统，但协调它们发育的机制仍然难以捉摸。我们发现激活转录因子3(ATF3)在斑马鱼的CPS、HPS和中胚层中高表达。ATF3−/−突变体表现为心房扩张型心肌病和高比例的未成熟髓系细胞。这些表现主要是由于前外侧板中胚层内CPS和HPS的分化受阻所致。在机制上，atf3靶向CEBPγ以抑制slc2a1a介导的葡萄糖利用。ATF3−/−突变体的高葡萄糖代谢通过改变氧化还原状态抑制了祖细胞的分化。因此，ATF3可以为CPS和HPS提供对血糖水平变化的代谢适应能力。我们的研究为ATF3通过调节糖代谢在协调CPS和HPS分化中的作用提供了新的见解。
ATF3 provides cardiac and hematopoietic progenitors with metabolic adaptive capacity for protection of differentiation potential. The cardiac and hematopoietic progenitors (CPs and HPs, respectively) in the mesoderm ultimately form a well-organized circulation system, but mechanisms that reconcile their development remain elusive. We found that activating transcription factor 3 (atf3) was highly expressed in the CPs, HPs, and mesoderm, in zebrafish. The atf3−/− mutants exhibited atrial dilated cardiomyopathy and a high ratio of immature myeloid cells. These manifestations were primarily caused by the blockade of differentiation of both CPs and HPs within the anterior lateral plate mesoderm. Mechanistically, Atf3 targets cebpγ to repress slc2a1a-mediated glucose utilization. The high rate of glucose metabolism in atf3−/− mutants inhibited the differentiation of progenitors by changing the redox state. Therefore, atf3 could provide CPs and HPs with metabolic adaptive capacity to changes in glucose levels. Our study provides new insights into the role of atf3 in the coordination of differentiation of CPs and HPs by regulating glucose metabolism.