Regulation Of Temporal And Spatial Gene Expression In Th

我们的单位感兴趣的是在昼夜节律的时间框架基因表达的调控模式的分子机制。在本财政年度，我们一直专注于我们的研究的上下文属性的昼夜E盒。这项工作很重要，因为E-box是一个非常混杂的DNA共有元件;因此，为了了解不同的信号通路如何在不同的E-box之间区分，需要对原型启动子进行系统分析。在这种情况下，血管加压素（AVP）启动子的分析导致发现一个推定的新的转录因子，似乎作为昼夜异源二聚体BMAL/CLOCK的共激活剂的功能。在第二个项目中，我们正在研究BMAL/CLOCK结合特定启动子的可能性，该启动子可以作为延迟装置来推迟cAMP介导的对在关键位置包含完美E-Box的其他昼夜节律基因的刺激。第三个项目涉及特定AP-1复合物对时钟控制基因的作用机制，这些基因似乎能够通过间接途径对BMAL/Clock介导的激活产生强大的抑制作用。 最后，我们最近取得了令人兴奋的观察，在啮齿动物系统中显示性别特异性，组织限制性和昼夜节律表达的产热相关基因。它的启动子正在被分析，以了解这种复杂的表达模式背后的机制。

Our Unit is interested in the molecular mechanisms underlying regulated patterns of gene expression in circadian time frames. During the current FY we have been focusing our studies on the contextual properties of circadian E-boxes. This work is important because the E-box is an extremely promiscuous DNA consensus element; thus, in order to understand how different signaling pathways can differentiate among different E-boxes, a systematic analysis of prototypic promoters is needed. The analysis of the vasopressin (AVP) promoter in this context led to the discovery of a putative novel transcription factor which appears to function as a co-activator of the circadian heterodimer BMAL/CLOCK. In a second project we are investigating the possibility that BMAL/CLOCK binding on specific promoters may act as a delaying device to postpone the cAMP mediated stimulation of other circadian genes that contain perfect E-Boxes at critical locations. A third project involves the mechanism of action of specific AP-1 complexes on clock controlled genes, which appear to be able to exert powerful suppression of BMAL/Clock mediated activation via an indirect pathway. Lastly, we have recently made the exciting observation of a thermogenesis-related gene displaying sex specific, tissue restricted and circadian expression in the rodent system. Its promoter is being analyzed to understand the mechanisms underlying such a complex pattern of expression.