PAX5调控LINE-1转录影响细胞衰老的机制研究

逆转录转座子LINE-1的异常激活导致宿主基因组不稳定并诱发衰老，在转录水平上如何抑制LINE-1过度表达是领域内关注的焦点。目前对LINE-1转录的研究主要集中于表观遗传调控，如5’-UTR区域的DNA甲基化、核小体修饰及异染色质相关因子如何抑制LINE-1转录。是否有转录因子直接参与对LINE-1的调控进而影响衰老发生及其具体调控机制尚未被深入阐明。申请人初步研究发现衰老细胞中LINE-1表达上调，基序富集分析并结合ChIP实验发现转录因子PAX5可结合至LINE-1的启动子区域并促进其转录，此外PAX5的过表达亦能促进细胞衰老，同时PAX5与长寿基因SIRT6相互作用，提示两者共同参与调控LINE-1活性。申请人拟利用多种衰老细胞模型阐明SIRT6-PAX5轴调控LINE-1的转录从而影响衰老的机制，为丰富LINE-1调控细胞衰老的理论及预防衰老相关疾病奠定理论基础。

Aberrant activation of the retrotransposon LINE-1 may induce cellular senescence by diminishing genomic stability through randomly integrating itself into host genomes, or by activating cGAS-STING-TBK1 innate immunity signaling pathway. The inhibitory mechanisms of LINE-1 transcription have received great attention. A number of studies have elucidated the mechanisms from different aspects including the DNA methylation in the 5’-UTR of LINE-1, histone modifications, heterochromatin associated factors. However, whether transcription factors directly participate in regulating age-associated LINE-1 transcription and the potential underlying mechanisms have not been elucidated. The applicant preliminary data indicate that LINE-1 transcription is upregulated, and enrichment analysis using public database indicates that there is PAX5 binding site in the 5’-UTR regions. Further ChIP assay also indicates that PAX5 is enriched in the 5’-UTR regions of LINE-1 elements in senescent cells. Preliminary mechanistic studies suggest that the longevity gene SIRT6 interacts with PAX5, and PAX5 is upregulated in adipose stem cells isolated from old donors while SIRT6 is down-regulated. The applicant proposes to further elucidate how the SIRT6-PAX5 axis regulates the transcription of LINE-1 retrotransposon, thereby affecting the onset of aging. Our work will lay the foundation of delaying the onset of aging by targeting SIRT6-PAX5 axis to inhibit LINE-1 retrotransposition.