A direct role for cholesterol in the regulation of transcription

在任何给定的细胞中，只有某些基因会被打开（或表达），并且是表达基因的特定组合决定了细胞的类型（例如肌肉，皮肤或神经细胞）。因此，基因表达的控制是细胞特性的核心。我们已经发现了一种多蛋白质复合物，它使用脂质来调节基因。这是非常不寻常的，因为脂质通常与细胞膜相关。我们的假设是，这种复合物使用脂质与细胞核内的其他因子形成接触，并且这个过程是在开启和关闭状态之间切换基因的核心。了解脂质如何调节基因将提供重要的见解，控制不同类型的细胞的形成的事件，也可能提供机会，使用脂质作用的药物来治疗疾病，导致异常的基因regulation.In本提案中，我们提出的证据表明，必需的脂质胆固醇可以发挥积极的作用，在关闭基因。我们发现胆固醇指导DNA上蛋白质之间相互作用的形成，然后阻止附近基因的表达。在这项提案中，我们将确定胆固醇关闭的基因。这将通过阻断胆固醇的产生，然后测量基因表达以及使用不再与胆固醇结合的突变蛋白质来实现。然后，我们将确定胆固醇如何改变DNA上蛋白质复合物的形成，并确定指导胆固醇开关作用的关键蛋白质。最后，将测试胆固醇对改变基因表达的酶的活性的影响。该提案的结果将增强我们对胆固醇在基因调控中的作用的理解，并为与细胞膜无关的脂质的功能提供新的见解。

In any given cell, only certain genes will be switched on (or expressed) and it is the specific combination of expressed genes that determines the type of cell (for example a muscle, skin or nerve cell). Thus, the control of gene expression lies at the heart of cellular identity. We have discovered a multi-protein complex that uses lipids to regulate genes. This is highly unusual because lipids are normally associated with cell membranes. Our hypothesis is that this complex uses lipids to form contacts with other factors within the cell nucleus and that this process is central to switching genes between an on and off state. Understanding how lipids regulate genes will provide important insights into the events that control the formation of different cell types and may also provide opportunities to use lipid-acting drugs to treat diseases that result from aberrant gene regulation.In this proposal we present evidence that the essential lipid cholesterol can play an active role in turning genes off. We find that cholesterol directs the formation of interactions between proteins on the DNA that then blocks expression of nearby genes. In this proposal we will determine the genes that are switched off by cholesterol. This will be achieved by blocking cholesterol production and then measuring gene expression and also by using mutant proteins that no longer bind to cholesterol. We will then determine how cholesterol changes the formation of protein complexes on the DNA and identify the critical proteins that are directing the action of the cholesterol switch. Finally, the effect of cholesterol on the activities of enzymes that alter gene expression will be tested. The outcomes of the proposal will enhance our understanding of the role of cholesterol in gene regulation and provide new insights into the function of lipids that are not associated with cellular membranes.