Dek通过H3组蛋白表观调控Akt1/2维持造血干细胞静息状态平衡的分子机制

表观调控基因Dek如何调控造血干细胞（HSCs）静息态是重要的科学问题。我们利用Dek条件敲除与转基因小鼠模型研究Dek在HSCs中的功能时发现：超表达和敲除Dek都会导致HSCs静息态失衡，超表达Dek导致HSCs阻滞于静息态，而敲除Dek则促进HSCs进入细胞周期。利用RNA-seq比较Dek敲除小鼠与对照小鼠HSCs基因表达变化，发现Akt1/2基因被显著上调，实验证明，Dek并不直接结合Akt1/2基因核心启动子调控转录，而Dek敲除使HSCs全基因组H3K27ac修饰显著增加，因此，我们提出Dek可能通过结合Akt1/2基因启动子区H3组蛋白抑制其H3K27ac修饰，维持Akt1/2基因低水平转录，进而抑制Akt/mTOR信号通路，维持HSCs静息状态平衡。本课题拟从分子及动物模型水平阐明Dek调控HSCs静息态的分子机制，研究结果对理解HSCs静息态表观调控网络具有重要意义。

Understanding the molecular mechanism how Dek maintains the quiescence of hematopoietic stem cells is an important scientific question. By using Dek HSC conditional knockout and transgenic mice, we found that either knockout or overexpression of Dek results in disturbing the homeostasis of HSCs. Dek overexpression blocks HSCs in quiescence(G0 Phase), while Dek knockout pushes HSCs into cell cycle. RNA-seq results showed that Akt1 and Akt2 are significantly up-regulated in Dek knockout HSCs. Further studies demonstrated Dek doesn’t directly bind to Akt1/2’s core promoter to activate their expression. However, Dek knockout LSK has a higher level of global H3K27ac modification. Since Dek can bind to Histone H3, we hypothesize that Dek represses Akt1/2 expression by maintaining a low level of H3K27ac on their core promoter. As a result of lowered Akt1/2 expression, Dek maintains the quiescence of HSCs by inhibiting Akt/mTOR signaling pathway. This project aims to elucidate the underlying molecular mechanism how Dek controls hematopoietic stem cell homeostasis using in vitro and in vivo models. The results generated by this project will extend our understanding how epigenetic network controls hematopoietic stem cells homeostasis.