DNA甲基转移酶3（Dnmt3）家族成员在斑马鱼造血干/祖细胞发育过程中的作用及分子机制研究

造血干细胞是一群能够自我更新，且能生成所有成熟血液细胞的多潜能干细胞。基于其重建整个血液系统的能力，造血干细胞移植已成功用于治疗白血病等恶性血液系统疾病。目前临床上面临的瓶颈问题是无法获得体外大量培养的自体可移植的造血干细胞。造成这种困境的原因在于我们对生物体内造血干细胞发育分化过程及其分子调控机制并不完全了解。我们在前期的研究工作中发现，DNA甲基转移酶3（Dnmt3）家族所有成员都在斑马鱼造血系统中特异性高表达，但其在造血系统发育过程中的作用以及调控机制并不完全清楚。本项目拟以斑马鱼为模式生物，综合利用多学科交叉，系统性的研究Dnmt3家族所有成员在造血干/祖细胞发育分化过程中的作用以及表观遗传调控机制。本项目的开展有利于从表观遗传学的角度加深对生物体内造血干细胞发育过程的了解，有助于完善现有的造血干细胞体外诱导和扩增方案，从而更好的促进这个在基础科学以及再生医学中至关重要问题的解决。

Hematopoietic stem cells (HSCs), which have the capacity to self-renew and replenish all blood lineages during the lifespan of an organism, are used in treatment of variety blood diseases including leukemia and anemia. The potential precise medical applications of HSCs, such as de novo generation of immune-competent personalized HSCs for transplantation, make it critical to fully understand how HSCs are generated in vivo. Although gene regulatory networks (GRNs) and signaling pathways controlling the specification of HSCs in embryonic development have been constructed, these are not yet fully completed and understood. Our preliminary data shows epigenetic factor DNA methyltransferase 3 (Dnmt3) family members are highly enriched in zebrafish hemogenic endothelium, but it’s not clear about their roles and precise mechanism of actions. This project will investigate the epigenetic roles of Dnmt3s in regulating zebrafish hematopoietic development. The outcome of the project is critical not only for a better mechanistic understanding of HSC emergence in vivo, but also, ultimately, for therapeutic applications, such as the treatment of inherited blood disorders through production of immune-competent, patient-specific HSCs from induced pluripotent stem cells(iPSC).