HBV通过干扰宿主19p13.11增强子与MAU2基因的染色质三维构象促进自身复制的机制研究

cccDNA的持续存在是慢乙肝难以治愈的重要原因。近期研究发现，以微染色体形式存在的cccDNA会在空间距离上靠近宿主染色体的转录活跃区域，提示HBV能够借助宿主基因组的转录开放环境促进自身复制。但具体作用方式尚未阐明。我们的前期工作证实cccDNA能与宿主染色体19p13.11增强子元件在空间距离上相互靠近，并受到增强子元件的直接调控。而增强子靶基因MAU2的表达却因此降低。因此，本项目将通过检测19p13.11增强子与靶基因MAU2的染色质空间构象变化，探究HBV对宿主基因MAU2染色质空间构象的破坏作用，明确HBV对MAU2基因表达的抑制；同时通过验证MAU2与HBV限制性因子SMC5/6复合体的关联性，阐述MAU2调控HBV复制转录的相关机制，揭示MAU2的抗病毒功能。本项目将进一步丰富HBV与宿主基因组空间互作的内涵，为了解HBV的转录调控机制以及寻找更多抗病毒因子提供新的思路。

The persistent existence of cccDNA is an important reason why chronic hepatitis B is difficult to cure. Recent studies have found that cccDNA in the form of micro chromosome is close to the transcriptional active region of host chromosome in spatial distance, suggesting that HBV can promote its own replication through the transcriptional open environment of host genome. However, the specific mode of action has not been clarified. Our previous work confirmed that cccDNA can be close to the enhancer element of host chromosome 19p13.11 in spatial distance, and is directly regulated by the enhancer element. However, the expression of mau2 was decreased. Therefore, this project will detect the changes of chromatin spatial conformation of 19p13.11 enhancer and target gene mau2, explore the destruction of HBV on the chromatin spatial conformation of host gene mau2, and clarify the inhibition of HBV on mau2 gene expression; at the same time, by verifying the correlation between mau2 and HBV restrictive factor Smc5 / 6 complex, elaborate the relevant mechanism of mau2 regulating HBV replication and transcription, and reveal the disease resistance of mau2 Toxic function. This project will further enrich the connotation of the spatial interaction between HBV and host genome, and provide new ideas for understanding the transcriptional regulation mechanism of HBV and looking for more antiviral factors.