Department of Biochemistry and Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
Blood. 2012 Mar 22;119(12):2789-98. doi: 10.1182/blood-2011-10-387902. Epub 2012 Feb 2.
Cited2 is a transcriptional modulator involved in various biologic processes including fetal liver hematopoiesis. In the present study, the function of Cited2 in adult hematopoiesis was investigated in conditional knockout mice. Deletion of Cited2 using Mx1-Cre resulted in increased hematopoietic stem cell (HSC) apoptosis, loss of quiescence, and increased cycling, leading to a severely impaired reconstitution capacity as assessed by 5-fluorouracil treatment and long-term transplantation. Transcriptional profiling revealed that multiple HSC quiescence- and hypoxia-related genes such as Egr1, p57, and Hes1 were affected in Cited2-deficient HSCs. Because Cited2 is a negative regulator of HIF-1, which is essential for maintaining HSC quiescence, and because we demonstrated previously that decreased HIF-1α gene dosage partially rescues both cardiac and lens defects caused by Cited2 deficiency, we generated Cited2 and HIF-1α double-knockout mice. Additional deletion of HIF-1α in Cited2-knockout BM partially rescued impaired HSC quiescence and reconstitution capacity. At the transcriptional level, deletion of HIF-1α restored expression of p57 and Hes1 but not Egr1 to normal levels. Our results suggest that Cited2 regulates HSC quiescence through both HIF-1-dependent and HIF-1-independent pathways.
Cited2 是一种转录调节剂，参与多种生物学过程，包括胎儿肝脏造血。在本研究中，使用 Mx1-Cre 对条件性敲除小鼠进行了 Cited2 在成人造血中的功能研究。Cited2 的缺失导致造血干细胞 (HSC) 凋亡增加、静止丧失和细胞周期增加，导致 5-氟尿嘧啶处理和长期移植后严重的重建能力受损。转录谱分析显示，多种 HSC 静止和缺氧相关基因，如 Egr1、p57 和 Hes1，在 Cited2 缺陷型 HSCs 中受到影响。因为 Cited2 是 HIF-1 的负调节剂，HIF-1 对于维持 HSC 静止是必需的，并且我们之前已经证明，降低 HIF-1α 基因剂量部分挽救了 Cited2 缺乏引起的心脏和晶状体缺陷，所以我们生成了 Cited2 和 HIF-1α 双敲除小鼠。在 Cited2 敲除 BM 中进一步删除 HIF-1α 部分挽救了受损的 HSC 静止和重建能力。在转录水平上，删除 HIF-1α 将 p57 和 Hes1 的表达恢复到正常水平，但 Egr1 则没有。我们的结果表明，Cited2 通过 HIF-1 依赖和非依赖途径调节 HSC 静止。
