Dynamics of nucleosome positioning and the role of chromatin in myogenesis

真核生物的DNA通过缠绕进入细胞核。 现在称为染色质的结构中的组蛋白。这种衰老会影响基因 含基因及其相关基因的染色质浓缩区域的调控 转录激活剂无法访问的调控元件。信号的调制 因此，染色质结构是转录调控的关键调节因子之一。 染色质的最基本单位是核小体，它由大约 146个碱基对的DNA包裹在组蛋白的八聚体周围。精准的 核小体在基因组功能调节区的定位可以直接 影响附近基因的转录调控。依赖三磷酸腺苷的染色质 重塑酶、组蛋白的翻译后修饰和DNA序列 其本身都与调节核小体在特定区域的定位有关 基因组的区域。我们建议调查每一个人的角色 果蝇核小体定位的调控机制 和人类基因组，并进一步开始阐明 染色质与转录因子在基因调控中的关系。我们将首先 研究染色质重塑酶如何被招募到 它们的靶点以及依赖于ATP的染色质重塑、组蛋白修饰和 利用培养果蝇DNA序列相互作用调节核小体定位 细胞。从这些在果蝇细胞中的实验中获得的见解将会是 应用于人类造血细胞的类似实验，该系统 参与谱系指定的转录因子网络已被广泛研究 学习。通过将核小体定位和染色质重塑的数据与 已经在这些细胞中建立了转录因子程序，我将能够研究 染色质与转录因子在调节细胞周期中的相互作用 细胞发育过程中的转录程序。这些研究将导致更大的 对核小体组织机制的理解 并进一步阐明染色质在细胞周期调控中的作用 抄写。

The DNA of eukaryotic organisms is pacl<aged into the nucleus by wrapping around histone proteins in a structure l<nown as chromatin. This pacl<aging can influence gene regulation with condensed chromatin regions containing genes and their associated regulatory elements that are inaccessible to transcriptional activators. The modulation of chromatin structure is therefore one of the key mediators of transcriptional regulation. The most basic unit of chromatin is the nucleosome, which consists of approximately 146 base pairs of DNA wrapped around an octamer of histone proteins. The precise positioning of nucleosomes in functional regulatory regions of the genome can directly influence the transcriptional regulation of nearby genes. ATP-dependent chromatin remodeling enzymes, post-translational modifications to histones and the DNA sequence itself have all been implicated in regulating the positioning of nucleosomes at specific regions of the genome. We propose to investigate the roles of each of these mechanisms in regulating the positioning of nucleosomes in the Drosophila melanogaster and human genomes and furthermore to begin to elucidate the relationship between chromatin and transcription factors in gene regulation. We will first investigate the basic questions of how chromatin remodeling enzymes are recruited to their targets and how ATP-dependent chromatin remodeling, histone modifications and DNA sequence interact to regulate nucleosome positioning by using cultured Drosophila cells. The insights obtained from these experiments in Drosophila cells will then be applied to analogous experiments in human hematopoietic cells, a system for which the network of transcription factors involved in lineage specification has been extensively studied. By integrating data on nucleosome positioning and chromatin remodeling with the already established transcription factor programs in these cells, I will be able to study the interactions between chromatin and transcription factors in regulating the transcriptional programs of cells during development. These studies will lead to a greater understanding of the mechanisms responsible for the organization of nucleosomes across the genome and further elucidate the role of chromatin in the regulation of transcription.