智障相关蛋白PQBP1调控mRNA选择性加尾的机制研究

Alternative polyadenylation (APA) in mRNA 3’-untranslated region (3’-UTR) is critical for mRNA stability, transport and translation and finely regulated in different tissues and cell conditions, but the underlining mechanism needs to be elucidated. Our preliminary research has shown that polyglutamine binding protein 1 (PQBP1), an X-linked intellectual disability related protein, interacts with the 3‘-processing complex CFIm, meanwhile knockout of PQBP1 alters APA and reduces cell proliferation . Thus, we hypnotize that PQBP1 functions as a novel APA regulator involved in cell proliferation. We have established PQBP1 knockout mouse model and we plan to dissect the molecular interaction between PQBP1 and CPSF6, a component of CFIm complex, identify the mRNA targets whose APA is regulated by PQBP1 using 3’-end targeted sequencing technique and analyze how these mRNA isoforms affect cell proliferation. This will give us a better understanding about the regulatory mechanism of alternation polyadenylation and its importancy under cell proliferation.

3'末端选择性加尾对mRNA的稳定、转运和翻译至关重, 该过程存在组织和细胞状态特异性，但其具体调控机制尚不明了。我们前期研究发现智障相关蛋白PQBP1和3'末端腺苷酸化切割核心组分CFIm复合物存在相互作用，敲除PQBP1会影响选择性加尾导致细胞增殖减慢。因此，我们推测PQBP1可能作为新的调控因子参与了细胞增殖过程选择性加尾过程的调节。在本申请项目中，我们拟利用PQBP1基因敲除小鼠模型，通过生化分析解析PQBP1与CFIm复合物蛋白CPSF6相互作用的分子基础，进行3’末端靶向的深度测序鉴定PQBP1调控的选择性加尾的靶mRNA，并进一步分析关键靶基因选择性加尾改变对细胞增殖能力的影响。该研究将有助于揭示3’末端选择性加尾的调控机制，并揭示选择性加尾在细胞增殖过程中的作用。

3'末端选择性加尾对mRNA的稳定、转运和翻译至关重, 该过程存在组织和细胞状态特异性，但其具体调控机制尚不明了。我们前期研究发现智障相关蛋白PQBP1和3'末端腺苷 酸化切割核心组分CFIm复合物存在相互作用，敲除PQBP1会影响选择性加尾导致细胞增殖 减慢。因此，我们推测PQBP1可能作为新的调控因子参与了细胞增殖过程选择性加尾过程 的调节。在本项目研究中，我们利用PQBP1基因敲除细胞和小鼠模型，通过生化、分子和生物信息等研究手段解析PQBP1 与参与mRNA选择性加尾的分子机制，并进一步分了PQBP1参与的APA调节对神经前体细胞增值和分化的影响。该项研究的成果帮助我们更好的了解神经系统中mRNA选择性加尾的特异调控机制，有助于解析孤独症等相关的神经疾病机制。