The role of chromatin regulation in normal and cancer stem cell self-renawal

干细胞（正常和癌细胞）的定义是它们自我更新的能力，以维持其功能。 数量，以及它们分化成不同细胞类型的能力。由于这些相互竞争的功能， 干细胞的基因组必须受到独特的调控-干细胞必须稳定地维持其基因表达 在自我更新的过程中，它们必须具有足够的灵活性，以彻底改变它们的基因表达模式。 在分化过程中。干细胞的基因表达模式受转录因子调控， 在细胞中表达的染色质调节剂。虽然控制干细胞自我更新的转录因子 在不同类型的干细胞之间，有越来越多的证据表明， 自我更新功能更广泛。最近，我们进行了一个RNAi筛选染色质调节剂， 在胚胎干细胞中的重要功能，并发现了68个基因与一系列敲除表型。我们 现在将在不同的干细胞类型，癌症干细胞中筛选这些因子的功能。使用两个鼠标 模型和人类癌细胞系，我们将确定癌症干细胞的染色质调节因子，目标是 找到新的靶点，以更有效地治疗癌症干细胞。我们将描述 在筛选中确定的染色质调节因子的分子功能，以更好地了解 染色质调节在癌症干细胞自我更新中的作用。接下来，我们将识别功能交互 在胚胎干细胞的转录因子和染色质调节因子中。虽然我们知道 关于在胚胎干细胞中起作用的转录因子网络， 它们与染色质调节因子相互作用以控制基因表达在很大程度上是未知的。通过检查 敲低染色质调节因子和多能性转录因子（单独或联合）的整体效应 组合）对基因表达的影响，我们希望确定对干细胞重要的新的功能相互作用。 自我更新随后，转录组或染色质调节子 功能将被检查。这些数据将有助于更好地理解干细胞基因 调控，这将最终用于未来的干细胞衍生疗法。

Stem cells (both normal and cancerous) are defined by their ability to self-renew, in order to maintain their numbers, and their ability to differentiate into distinct cell types. Because of these competing functions, the genome of stem cells must be uniquely regulated ~ stem cells must stably maintain their gene expression pattem during self-renewal, but must be flexible enough to drastically alter their gene expression pattern during differentiation. The gene expression patterns of stem cells are regulated by transcription factors and Chromatin regulators expressed in the cell. While transcription factors that control stem cell self-renewal vary considerably between different types of stem cells, there is increasing evidence that chromatin regulators of self-renewal function more broadly. Recently we performed an RNAi screen for chromatin regulators with mportant functions in embryonic stem cells and found 68 genes with an array of knockdown phenotypes. We will now screen these factors for function in a different stem cell type, cancer stem cells. Using both mouse models and human cancer cell lines, we will identify chromatin regulators of cancer stem cells, with the goal of identifying novel targets for more effective therapies that target the cancer stem cells. We will characterize the molecular functions of chromatin regulators identified in the screen to gain a greater understanding of the roles of chromatin regulation in cancer stem cell self-renewal. Next, we will identify functional interactions among transcription factors and chromatin regulators in embryonic stem cells. Although much is known about the network of transcription factors that function in embryonic stem cells, the mechanisms by which they interact with chromatin regulators to control gene expression are largely unknown. By examination of the global effects of knocking down chromatin regulators and pluripotency transcription factors (alone or in combination) on gene expression, we hope to identify novel functional interactions important for stem cell self-renewal. Subsequently, the mechanisms by which groups of transcription or chromatin regulators function together will be examined. These data should lead to a greater understanding of stem cell gene regulation, which will ultimately be useful for future stem cell-derived therapies.