Combinatorial regulation of gene expression by u ORFs and microRNAs in Drosophila

果蝇中uORF和microRNA对基因表达的组合调控

Gene expression is tightly controlled at multiple levels by different categories of cis-regulatory elements(CREs)and transacting factors(TAFs).Two different regulators might have additive or even synergistic effects,enabling robust repression or activation of target gene expression(i.e.f the"fail-safe"regulation).Alternatively,two regulators might antagonistically regulate the same targets,which seems futile,but could stabilize gene expression.As a transcript could be regulated by multiple mechanisms,the combinatorial use of different categories of CREs and TAFs might be prevalent in modulating the function and fate of an mRNA[1,2].

生物体为了确保发育程序的准确性或维持细胞内环境的稳定,会利用不同类型的顺式调控元件和反式作用因子在多个层面精细调控基因表达.近年来我们对多种调控元件和因子的作用机制和生物学功能有了深入了解,但对它们组合使用的调控效果知之甚少.本文解析了果蝇怎样通过对上游开放阅读框(uORF)和microRNA的组合使用在转录后水平上调控mRNA的功能和命运.本文首先分析了uORF和microRNA靶位点在基因组中的分布规律,发现mRNA倾向于被两者共同调控("u+m+"mRNA).这些"u+m+"mRNA比其他mRNA具有更低的翻译效率,其中uORF起主要抑制作用,microRNA仅起辅助作用.同时,研究发现"u+m+"mRNA具有较低的稳定性,除了受uORF和microRNA的影响之外,还由于"u+m+"mRNA招募多聚腺苷酸结合蛋白(PABP)的能力更弱,而且在编码区有更多的稀缺密码子.本研究揭示了从转录后和翻译水平上调控mRNA命运和功能的不同途径之间的紧密关联,为深入阐释基因表达的规律提供了新的见解.