Wang Haifang, Fan Zenghua, Zhao Meng, Li Juan, Lu Minghua, Liu Wei, Ying Hao, Liu Mofang, Yan Jun
CAS-MPG Partner Institute for Computational Biology, Shanghai 200031, China.
Institute of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai 200031, China.
Sci Rep. 2016 Feb 22;6:21598. doi: 10.1038/srep21598.
The roles of miRNAs as important post-transcriptional regulators in the circadian clock have been suggested in several studies. But the search for circadian miRNAs has led to disparate results. Here we demonstrated that at least 57 miRNA primary transcripts are rhythmically transcribed in mouse liver. Most of these transcripts are under the regulation of circadian transcription factors such as BMAL1/CLOCK and REV-ERBα/β. However, the mature miRNAs derived from these transcripts are either not oscillating or oscillating at low amplitudes, which could explain the inconsistency of different circadian miRNA studies. In order to show that these circadian primary transcripts can give rise to miRNAs with circadian functions, we over-expressed one of them, miR-378, in mouse by adenovirus injection. We found a significant over-representation of circadian oscillating genes under-expressed by miR-378 over-expression in liver. In particular, we observed that miR-378 modulates the oscillation amplitudes of Cdkn1a in the control of cell cycle and Por in the regulation of oxidation reduction by forming partnership with different circadian transcription factors. Our study suggests that circadian transcription of miRNA at primary transcript level can be a good indicator for circadian miRNA functions.
多项研究表明，微小RNA（miRNA）作为昼夜节律钟重要的转录后调节因子发挥作用。但对昼夜节律miRNA的搜寻却得到了不同的结果。在此，我们证明，在小鼠肝脏中至少有57种miRNA初级转录本有节律地转录。这些转录本大多受昼夜节律转录因子如BMAL1/CLOCK和REV-ERBα/β的调控。然而，源自这些转录本的成熟miRNA要么不发生振荡，要么振荡幅度较低，这可以解释不同昼夜节律miRNA研究结果的不一致性。为了证明这些昼夜节律初级转录本能够产生具有昼夜节律功能的miRNA，我们通过腺病毒注射在小鼠体内过表达其中一种，即miR-378。我们发现，在肝脏中，miR-378过表达导致表达下调的昼夜节律振荡基因显著富集。特别是，我们观察到miR-378通过与不同的昼夜节律转录因子形成伙伴关系，在细胞周期调控中调节Cdkn1a的振荡幅度，在氧化还原调节中调节Por的振荡幅度。我们的研究表明，miRNA在初级转录本水平的昼夜节律转录可以作为昼夜节律miRNA功能的良好指标。
