Spindlin1及其家族成员蛋白表观遗传调控乙肝病毒的作用及机制研究

Spindlin1，是Spin/Ssty蛋白家族成员之一，由三个类Tudor结构域串联构成，主要通过第一和第二个结构域识别H3R8me2和H3K4me3修饰来激活下游基因的转录。然而，目前关于Spindlin1抑制下游基因转录的功能还知之甚少，尤其是Spindlin1第三个结构域的生物学功能国内外尚无报道。此外，关于Spin家族中其它成员的生物学功能也几乎没有报道。在前期工作中，我们发现Spindlin1可以通过它的第三个类Tudor结构域与HBV调控蛋白HBx互作，且成功解析了Spindlin1-HBx复合物的晶体结构。更重要的是，我们发现Spindlin1可以抑制HBV基因的转录。据此，我们拟揭示Spindlin1第三个结构域的生物学功能和结构基础，深入探究Spin家族成员表观遗传调控HBV及其它核内病毒的分子机制，并由此设计小分子药物，以期为临床上HBV的预防和治疗提供新的候选药物。

Spindlin1, a member of the Spin/Ssty family of proteins, possesses a novel arrangement of the Tudor repeat domain fold. Spindlin1, as a histone reader, mainly promote the downstream signaling factor activity through recognizing H3K4me3 and H3R8me2 by an aromatic cage of the second and first Tudor-like domain respectively. However, little is known about the functions of Spindlin1 silencing downstream signaling gene transcription. Moreover, functions of the third Tudor-like domain of spindlin1 is totally unknown. In addition, little has been reported about the biological functions of the other members of the Spin family. In our previous work, we have identified that Spindlin1 could interact with HBx directly through its third Tudor-like domain, and we have also solved the crystal structure of SPIN1(50–262) in complex with HBx(1-20) at 1.9 Å. More importantly, we found that Spindlin1 was able to repress HBV transcription. Based on these, we apply for revealing the biological functions and corresponding structural basis of the third Tudor-like domain of spindlin1, and uncovering the mechanisms underlying Spin family proteins epigenetically regulating the transcription of HBV and other viruses replicating in the nucleus. Based on these findings, we aim to identify small molecules that inhibiting HBV and provide new drug candidates for HBV prevention and treatment.