Dynamic global analysis of transcription reveals the role of mi RNAs in synergistic stabilization of gene expression  

通过对基因转录的动态和全局分析揭示miRNAs协同稳定基因表达的作用

作　　者：Fuqiang Ma Guang-An Lu Qingjian Chen Yongsen Ruan Xin Li Xuemei Lu Chunyan Li 麻富强;陆广安;陈青建;阮永森;李欣;吕雪梅;李春燕(School of Life Sciences,Sun Yat-sen University.Guangzhou 510275,China;Beijing Advanced Innovation Center for Big Data-Based Precision Medicine,School of Medicine and Engineering,and Key Laboratory of Big Data-Based Precision Medicine(Ministry of Industry and Information Technology),Beihang University,Beijing 100191,China;State Key Laboratory of Genetic Resources and Evolution&CAS Center for Excellence in Animal Evolution and Genetics,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China;State Key Laboratory of Molecular Developmental Biology,Institute of Genetics and Developmental Biology,Chinese Academy of Sciences,Beijing 100101,China;Key Laboratory of Genomic and Precision Medicine,Beijing Institute of Genomics,Chinese Academy of Sciences,Beijing 100101,China;University of Chinese Academy of Sciences,Beijing 100049,China)

机构地区：[1]School of Life Sciences,Sun Yat-sen University.Guangzhou 510275,China [2]Beijing Advanced Innovation Center for Big Data-Based Precision Medicine,School of Medicine and Engineering,and Key Laboratory of Big Data-Based Precision Medicine(Ministry of Industry and Information Technology),Beihang University,Beijing 100191,China [3]State Key Laboratory of Genetic Resources and Evolution&CAS Center for Excellence in Animal Evolution and Genetics,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China [4]State Key Laboratory of Molecular Developmental Biology,Institute of Genetics and Developmental Biology,Chinese Academy of Sciences,Beijing 100101,China [5]Key Laboratory of Genomic and Precision Medicine,Beijing Institute of Genomics,Chinese Academy of Sciences,Beijing 100101,China [6]University of Chinese Academy of Sciences,Beijing 100049,China

出　　处：《Science Bulletin》2020年第24期2130-2140,M0006,共12页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China (31801094 to C.L. and 31771416 to X.L.);the Key Research Program of the Chinese Academy of Sciences (KFZD-SW-220-1 to X.L.);CAS “Light of West China” Program (to X.L.);the National Natural Science Foundation of China (31900417 to G.L.);the National Key Basic Research Program of China (2014CB542006 to C.L.);China Postdoctoral Science Foundation (2019M653162 to G.L.)。

摘　　要：Buffering exogenous perturbation is crucial to maintain transcriptional homeostasis during development.While mi RNAs have been speculated to play a role in stability maintenance, previous studies seeking to check this conjecture focused on measurements of transcript levels at steady state or involved individual mi RNA targets. We measured whole-genome expression dynamics by introducing a transient perturbation and establishing a perturbation and recovery system in Drosophila larvae. We inhibited all transcription and assayed transcriptomes at several time points during recovery from inhibition. We performed these experiments in the wild type and mi RNA-deficient genetic backgrounds. Consistent with theories about mi RNAs’ function in stabilizing the transcriptome, we find that attenuating mi RNA expression leads to weak impairment in degradation of targets but strong destabilization of target genes when transcription is re-activated. We further fitted a model that captures the essential aspects of transcription dynamics in our experiments and found that the mi RNA target transcripts uniformly overshoot the original steady state as they recover from a general inhibition of transcription if global mi RNA levels are reduced. Collectively, our results provide experimental evidence for the idea that mi RNAs act cumulatively to stabilize the transcriptional regulatory network. We therefore found a promising approach to assess the effect of these molecules on transcription dynamics.缓冲外界干扰,维持转录组稳定,对生物个体发育至关重要.曾有关于mi RNA维持转录组稳定性的猜测,但前期工作大多关注稳定态时基因的转录调控或单个mi RNA靶基因的表达改变.本研究通过引入一个瞬时的干扰,利用黑腹果蝇的幼虫建立了一个干扰和恢复系统,在全基因组水平衡量了基因表达的动态变化.分别在野生型和mi RNA缺少的果蝇中,在全面抑制转录后,测量转录恢复阶段不同时间点的转录组.与mi RNA维持转录组稳定性的理论猜测一致,研究发现mi RNA水平的降低可导致靶基因降解的轻微降低,但是在转录激活后,靶基因表达水平的稳定性被破坏.通过将实验观察数据与转录动态的数学模型拟合发现,在转录全面抑制后的恢复阶段,全局性mi RNA水平的减低可导致mi RNA靶基因的全局上调.本研究提示mi RNA可通过累加效应维持转录调控网络的稳定性.

关 键 词：miRNAs TRANSCRIPTOME PERTURBATION Stability Synergistic effects 

分 类 号：Q75[生物学—分子生物学]