Ghislain Breton, Ph.D.

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Research Information

Mechanistic basis of gene expression control by the circadian system

糖尿病，癌症和心脏病发作等复杂疾病与多种因素有关，随着时间的流逝，它们相互影响并导致最终诊断。人类基因组的解码表明，我们身体的每个细胞都有能力表达32,000个左右独特基因的多个副本。尽管每种疾病都意味着这些基因的一部分，但通常需要进行整体情况才能正确设计治疗剂。我们的实验室对我们的基因组的复杂性和组织感兴趣，以及对疾病状态中作用因素的鉴定。为了实现这一目标，我们期待通过描述如何及时地精心策划这些基因的表达来简化这一复杂的图像。我们和其他人发现，基因在一天中的特定时间内以束束表达，这些束与特定的细胞功能有关。从细胞的角度来看，该观察结果很有意义，因为看来细胞已经学会了在时间特定函数中进行协调。数十亿年来，居住在地球上的生物已经每天经过每天反复发生的温度和光变化，随着行星在其轴上旋转。夜间和白天周期的持续重复是少数稳定参数之一，当然是生命进化的重要因素。这种环状行为在睡眠/唤醒，体温和血压中的每日节奏中都显着，在所有水平的生物学上都很明显。 In order to anticipate sunrise and sunset and to measure seasonal changes in day length, animals, plants and certain bacteria evolved an internal mechanism to track time. The circadian clock consists of a series of interconnected molecular events that last approximately 24 hours. This master regulator is orchestrating metabolism and physiology.

Using a combination of functional genomic and bioinformatics approaches, we recently demonstrated in the model systemArabidopsis thalianathat the regulation of at least 89% of the expressed genes displayed daily oscillations when under light, temperature or circadian cycles. These factors are the three main external and internal marks of daily timing in nature. This result suggests time-dependent transcriptional regulation is a central factor in daily regulation of physiology. Our current model of the eukaryotic circadian system is a core subset of transcription factors (TF) that are organized in an auto-regulatory feedback loop. Each one of these TFs is also rhythmically regulating specific groups of non-clock genes at specific times of the day. Those genes are categorized as first order clock-controlled genes (CCGs). Since some of those are also TFs, they create a second wave of rhythmically regulated genes called second order CCGs and so on. Light- and temperature-controlled networks are intrinsically embedded in this large circadian network creating a complex interplay of transcriptional activation and repression. We believe genomics and bioinformatics offer new possibilities that can quickly drive forward our understanding of the role that light, temperature and the circadian clock play over the regulation of other TFs. Constructing a detailed map of the clock-driven cis-regulatory transcriptional network will ultimately lead us to understand, with a global perspective, the importance of daily rhythms in healthy cells and tissues. From a medical point of view, this knowledge will give us the opportunity to develop the tools to monitor circadian-controlled physiological events in order to use these as diagnostic markers. These markers could then be used to identify potential cellular perturbations and to help treat complex metabolic diseases.

Our lab utilizes several model organisms from Arabidopsis to Zebrafish with the single goal to understand organization of gene regulation on a daily basis by the circadian system. We are currently exploring three areas:

1. Using a combination of Genomics and Bioinformatics to unravel the animal circadian-controlled gene network using Zebrafish as a model system.
2. Developing novel functional genomic tools for large scale survey of gene expression regulation.
3. 与实时生物发光成像结合进行化学筛选，以鉴定昼夜节律系统中的敏感节点。

出版物

出版信息

REFERENCES

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