Atypical patterns of circadian clock gene expression in human peripheral blood mononuclear cells
Atypical patterns of circadian clock gene expression in human peripheral blood mononuclear cells
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DOI：
10.1007/s00109-005-0697-6
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发表时间：
2005-09-01
影响因子：
4.7
通讯作者：
Milano, G
中科院分区：
文献类型：
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作者：
Teboul, M;Barrat-Petit, MA;Milano, G
所有哺乳动物（包括人类）都观察到生理和行为的昼夜节律（类似于 24 小时）。这些节律是由位于下丘脑和大多数外周组织的生物钟产生的。时钟基因是生物钟的重要组成部分，其中一些基因的突变或多态性与人类的昼夜节律紊乱有关。然而，有关人类时钟基因表达的信息仍然非常有限。外周血单核细胞 (PBMC) 是在分子水平上非侵入性研究人体生物钟的理想材料。在本研究中，我们分析了 24 小时周期内 10 名健康人的 PBMC 中三个关键时钟基因 PER2、BMAL1 和 REV-ERB α 的表达。研究发现，所有受试者的 PER2 和 BMAL1 在整个明暗周期中都会振荡。有趣的是，尽管褪黑激素和皮质醇分泌模式正常，但两组受试者的平均 PER2 和 BMAL1 末相显着不同。 BMAL1 以与 PER2 大致相同的相位振荡，而不是如先前在其他外周组织中获得的数据所预期的反相位。此外，人类 PBMC 中 PER2 和 BMAL1 的这种不寻常的相位关系与 REV-ERB α 的恒定表达相关，REV-ERB α 是 BMAL1 的关键调节因子，在许多其他系统中具有高度节律性。这些结果揭示了时钟基因表达模式的不同时间型的存在，并提出了人类 PBMC 中的特定调节机制。
Circadian (similar to 24 h) rhythms in physiology and behaviour are observed in all mammals, including humans. These rhythms are generated by circadian clocks located in the hypothalamus and also in most peripheral tissues. Clock genes are essential components of circadian clocks, and mutations or polymorphisms within several of them have been associated with circadian disorders in humans. However, information about human clock gene expression has remained very limited. Peripheral blood mononuclear cells (PBMCs) represent an ideal material to investigate non-invasively the human clock at the molecular level. In the present study, we analysed the expression of three key clock genes, PER2, BMAL1 and REV-ERB alpha in PBMCs from ten healthy humans over a 24-h cycle. PER2 and BMAL1 were found to oscillate throughout the light-dark cycle in all subjects. Interestingly, despite normal melatonin and cortisol secretion patterns, two groups of subjects could be distinguished with significantly different mean PER2 and BMAL1 acrophases. BMAL1 oscillated with approximately the same phase as PER2, instead of being anti-phasic as anticipated from data previously obtained in other peripheral tissues. Furthermore, this unusual phase relationship of PER2 and BMAL1 in human PBMCs was associated with a constant expression of REV-ERB alpha, a crucial regulator of BMAL1, which is highly rhythmic in many other systems. These results reveal the existence of different chronotypes of clock gene expression patterns and suggest specific regulatory mechanisms in human PBMCs.