任何經(jīng)歷時差的人,，都會了解到生理時鐘正常的重要性,。人體經(jīng)由視網(wǎng)膜光受體感應(yīng)光線，再將訊息傳遞至腦部的視叉上核,。周邊組織的階段調(diào)整可以讓身體不同的生理時鐘都能跟上相同的時間,。將生理時鐘同步化的方法，可能是間接經(jīng)由依賴SCN的生理時鐘來調(diào)整,，例如攝食的周期或體溫,。但是，科學(xué)家還不清楚如何在分子層級將所有時鐘同步調(diào)整,。其中一個重要的問題是,，周邊組織中周期地表現(xiàn)的基因，是受到局部的生理時鐘控制,，還是由全身的生理時鐘所控制,。
根據(jù)一項發(fā)表于本周PLoS Biology中的新研究，研究人員Benoit Kornmann和Ueli Schibler等人研究肝臟的生理時鐘，并試著回答這個問題,。
為了確定這些基因是受到局部還是全身的控制,，研究人員制造出一種小鼠品系，可以依照不同的研究條件,，啟動肝臟的生理時鐘,。
作者修改了一種名為REV-ERBa的轉(zhuǎn)錄因子，可抑制時鐘基因Bmal1而關(guān)閉生理時鐘的基因表現(xiàn),。經(jīng)過修改的基因帶有四環(huán)素敏感元素(TREs),，可以對于四環(huán)素和類似的抗生素產(chǎn)生反應(yīng)。帶有這個修改基因的小鼠與帶有可以活化肝細胞中TREs的基因之小鼠交配,。
牠們產(chǎn)下的子代被喂食類似四環(huán)素的doxycyline (Dox),，結(jié)果肝細胞中的REV-ERBa仍未活化，且Bmal1基因的功能正常,。當轉(zhuǎn)基因小鼠缺乏Dox 時,，會過度表現(xiàn)REV-ERBa，且Bmal1是不活化的,，因此有效地關(guān)閉了肝臟的生理時鐘,。
研究人員進一步發(fā)現(xiàn)，環(huán)境中的提示,，包括升高的溫度和氧化壓力,，會活化熱休克因子1(HSF1)。當感應(yīng)到代謝出現(xiàn)節(jié)律上的變化時,，HSF1可調(diào)節(jié)節(jié)律基因mPer2的表現(xiàn),，而使周邊組織的時鐘同步化。
(資料來源 : Bio.com)
部分英文原文：
System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock
Benoît Kornmann1, Olivier Schaad2, Hermann Bujard3, Joseph S. Takahashi4, Ueli Schibler1*
1 Department of Molecular Biology, University of Geneva, Geneva, Switzerland, 2 Department of Biochemistry, University of Geneva, Geneva, Switzerland, 3 Zentrum für Molekulare Biologie, Universität Heidelberg, Heidelberg, Germany, 4 Howard Hughes Medical Institute, Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, United States of America
The mammalian circadian timing system consists of a master pacemaker in neurons of the suprachiasmatic nucleus (SCN) and clocks of a similar molecular makeup in most peripheral body cells. Peripheral oscillators are self-sustained and cell autonomous, but they have to be synchronized by the SCN to ensure phase coherence within the organism. In principle, the rhythmic expression of genes in peripheral organs could thus be driven not only by local oscillators, but also by circadian systemic signals. To discriminate between these mechanisms, we engineered a mouse strain with a conditionally active liver clock, in which REV-ERBα represses the transcription of the essential core clock gene Bmal1 in a doxycycline-dependent manner. We examined circadian liver gene expression genome-wide in mice in which hepatocyte oscillators were either running or arrested, and found that the rhythmic transcription of most genes depended on functional hepatocyte clocks. However, we discovered 31 genes, including the core clock gene mPer2, whose expression oscillated robustly irrespective of whether the liver clock was running or not. By contrast, in liver explants cultured in vitro, circadian cycles of mPer2::luciferase bioluminescence could only be observed when hepatocyte oscillators were operational. Hence, the circadian cycles observed in the liver of intact animals without functional hepatocyte oscillators were likely generated by systemic signals. The finding that rhythmic mPer2 expression can be driven by both systemic cues and local oscillators suggests a plausible mechanism for the phase entrainment of subsidiary clocks in peripheral organs.
英文全文鏈接：http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050034
