Involvement of posttranscriptional regulation of Clock in the emergence of circadian clock oscillation during mouse development
Involvement of posttranscriptional regulation of Clock in the emergence of circadian clock oscillation during mouse development
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DOI：
10.1073/pnas.1703170114
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发表时间：
2017-08
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通讯作者：
Yasuhiro Umemura;Nobuya Koike;Munehiro Ohashi;Yoshiki Tsuchiya;Q. Meng;Y. Minami;Masayuki Hara;Moe Hisatomi;K. Yagita
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作者：
Yasuhiro Umemura;Nobuya Koike;Munehiro Ohashi;Yoshiki Tsuchiya;Q. Meng;Y. Minami;Masayuki Hara;Moe Hisatomi;K. Yagita
Significance Circadian clocks reside in each cell level throughout the body in mammals. Intrinsic cellular circadian clocks develop cell autonomously during the cellular differentiation process. However, mechanisms controlling the emergence of cellular circadian clock oscillation in vivo are not fully understood. Here, we show that Dicer/Dgcr8-mediated posttranscriptional mechanisms control the CLOCK protein expression in both mouse fetal hearts and in vitro differentiating ES cells, which contributes to the emergence of circadian clock in mammalian cells. This event occurs after cell lineage determination into hearts or loss of pluripotent stem cell markers in differentiating ES cells, suggesting the cellular differentiation-coupled clock development may be conducted by a two-step program consisting of cellular differentiation and subsequent establishment of circadian transcriptional/translational feedback loops. Circadian clock oscillation emerges in mouse embryo in the later developmental stages. Although circadian clock development is closely correlated with cellular differentiation, the mechanisms of its emergence during mammalian development are not well understood. Here, we demonstrate an essential role of the posttranscriptional regulation of Clock subsequent to the cellular differentiation for the emergence of circadian clock oscillation in mouse fetal hearts and mouse embryonic stem cells (ESCs). In mouse fetal hearts, no apparent oscillation of cell-autonomous molecular clock was detectable around E10, whereas oscillation was clearly visible in E18 hearts. Temporal RNA-sequencing analysis using mouse fetal hearts reveals many fewer rhythmic genes in E10–12 hearts (63, no core circadian genes) than in E17–19 hearts (483 genes), suggesting the lack of functional circadian transcriptional/translational feedback loops (TTFLs) of core circadian genes in E10 mouse fetal hearts. In both ESCs and E10 embryos, CLOCK protein was absent despite the expression of Clock mRNA, which we showed was due to Dicer/Dgcr8-dependent translational suppression of CLOCK. The CLOCK protein is required for the discernible molecular oscillation in differentiated cells, and the posttranscriptional regulation of Clock plays a role in setting the timing for the emergence of the circadian clock oscillation during mammalian development.
